Lungs of 2-Year-Old Reveal Ancient Origins of Measles Virus

Lungs of 2-Year-Old Reveal Ancient Origins of Measles Virus

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The world’s oldest known measles sample has been discovered in the lungs of a girl who died in 1912 and scientists now suggest the ancient virus jumped from animals to humans around 300 BC, making the disease in people much older than previously believed.

According to a summary of the new findings in Science, a team of researchers has made ´a groundbreaking´ new find relating to the history of measles after the oldest sample ever discovered was found in the preserved lung of a two-year-old girl who had died in 1912 from measles. The remains of the little girl were found in the basement storage facility of the Museum of Medical History in Berlin and she had never before been tested, but the new study reveals that measles may have emerged 1,000 years earlier than currently believed.

Tracking the Ancient Origins Of Measles

The new study was based on analysis of “the oldest known sample of the measles virus known to science” and, according to a feature in Science Mag , this microcosmic bacterial discovery always ´promised´ new insights about the evolution of the disease throughout history. Until this new paper, researchers had incorrectly thought the measles virus had first emerged between 400 AD and 1400 AD but the new analysis suggests it may have first appeared a thousand years earlier, as early as 300BC.

Researcher and co–author of the new paper, Professor Sebastien Calvignac-Spencer, told Science that his team isolated RNA from the oldest measles virus, “by more than 40 years”. Previously, the oldest known sample of a measles virus dated back to 1954 and had been used to develop the first measles vaccine, but this newly tested lung sample had been preserved in the basement in a formaldehyde solution known as formalin which preserved the virus in near perfect conditions for testing.

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The preserved lungs of a girl who died from measles in 1912. Credit: KAI KUPFERSCHMIDT/SCIENCE

The 9th Century Arabian Bacterial Explorer

As for the origins of measles, around 10,000 years ago people started establishing hunting, fishing and agricultural settlements which would shape the future of human civilization, but people were now living closer together in unsanitary communities and many animal diseases jumped species. The new paper suggests the virus came from sheep and goats around 300 BC and, while not fully proven, it is suspected to have migrated to humans as we increasingly populated cities, subsequently creating less space between humans and livestock.

According to a paper on QScience, the first description of measles dates back to the ninth century AD when Persian physician, Al-Razi, wrote his treatise on Smallpox and Measles in 865 AD. This genius physician died in Rayy in 925 AD but is famed in medical circles for having coined the term “sudden death” in Arabic 1000 years ago, and for having first identified measles as an independent infection, differing from smallpox.

It was only in 1757 that Francis Home, the Scottish physician, demonstrated that the infection was caused by an agent in the blood and after a 1964 breakout in Boston, John F. Enders and Dr Thomas C. Peebles isolated the measles virus in the patient’s blood which soon after led to a vaccine.

European depiction of the Persian (Iranian) doctor Al-Razi, in Gerardus Cremonensis "Recueil des traités de médecine" 1250-1260. ( )

City Dwellers Amplified the Effect of Measles

Professor Sebastien Calvignac-Spencer wrote in the new paper that the virus would have ideally needed populations of between between 250,000 and a million people to spread widely and not just die out, and that the biggest cities in the world emerged around the fourth century AD, and as an example, the researcher said as many as “a million people lived in Rome around that time”. He added that the virus depends on large populations to keep itself alive as it requires exposure to new hosts, which they say can be difficult because once a person's been infected by the virus, they develop a lifetime immunity to it.

The Daily Mail article refers to the Great Ormond Street Hospital , who say measles has been resurgent in the last several years, with more than 9.7 million documented cases in 2018 and 142,300 deaths, the majority of which were children under four years old. And on the back of this, it advises readers that measles can be prevented by receiving “two vaccinations, the first at 13 months old and the second at three years and four months to five years old.”

The measles virus. Credit: nobeastsofierce / Adobe Stock

The Way It Used To Be

To cover myself before I write my last paragraph, I must first state that in no way whatsoever am I either endorsing or advising against the somewhat controversial combined Measles Mumps Rubella vaccination, but I cannot reject my own personal experience with the disease and take stock of how much things have changed over the last two or three decades.

When I was a lad, we went to school and caught the measles and got the customary week off school, which we spent watching films on VHF tapes. We would eventually go back to school to pass the virus along to the next child we ´tagged´ in the playground, and so we all quickly, and together as a community, became immunized for life in one or two months, keeping alive the micro-organism that leaped from animals to humans in ancient days.

Ancient History of Lyme Disease in North America Revealed with Bacterial Genomes

A team of researchers led by the Yale School of Public Health has found that the Lyme disease bacterium is ancient in North America, circulating silently in forests for at least 60,000 years—long before the disease was first described in Lyme, Connecticut, in 1976 and long before the arrival of humans.

For the first time, the full genomes of the Lyme disease bacterium, Borrelia burgdorferi, were sequenced from deer ticks to reconstruct the history of this invading pathogen.

The finding shows that the ongoing Lyme disease epidemic was not sparked by a recent introduction of the bacterium or an evolutionary change—such as a mutation that made the bacterium more readily transmissible. It is tied to the ecological transformation of much of North America. Specifically, forest fragmentation and the population explosion of deer in the last century have created optimal conditions for the spread of ticks and triggered this ongoing epidemic.

Katharine Walter conducted the research while a doctoral student at Yale School of Public Health and is lead author of the study published in Nature Ecology and Evolution.

“The Lyme disease bacterium has long been endemic,” she said. “But the deforestation and subsequent suburbanization of much of New England and the Midwest created conditions for deer ticks—and the Lyme disease bacterium—to thrive.”

Lyme disease is the most common vector-borne disease in North America. Since it was first described in the 1970s, the disease has rapidly spread across New England and the Midwest. Reported cases of Lyme disease have more than tripled since 1995 and the Centers for Disease Control and Prevention now estimate that more than 300,000 Americans fall ill each year.

The team turned to genomics to reveal the bacterium’s origins. By comparing B. burgdorferi genomes collected from different areas and over a 30-year period, the team built an evolutionary tree and reconstructed the history of the pathogen’s spread.

Researchers collected deer ticks, vectors of B. burgdorferi, from across New England. They focused sampling efforts in areas predicted to be sources of the epidemic—Cape Cod and areas around Long Island Sound. Over 7,000 tick were collected from these areas during the summer of 2013. To extend the spatial scope of the study, collaborators in the South, Midwest, and across Canada contributed ticks to the team.

Using a method the team previously developed to preferentially sequence bacterial DNA (and avoid sequencing only DNA from the tick), the researchers sequenced 148 B. burgdorferi genomes. Earlier studies of the evolutionary history of B. burgdorferi have relied upon short DNA markers rather than full genomes. Reading the one million letters of the full bacterial genome allowed the team to piece together a more detailed history. The team drew an updated evolutionary tree which showed that the bacterium likely originated in the northeast of the United States and spread south and west across North America to California.

Birds likely transported the pathogen long distances to new regions and small mammals continued its spread. Imprinted on the bacterial genomes was also a signature of dramatic population growth. As it evolved, it seemed to have proliferated.

The tree was also far older than the team had expected—at least 60,000 years old. This means that the bacterium existed in North America long before the disease was described by medicine and long before humans first arrived in North America from across the Bering Strait (about 24,000 years ago)

This findings clarify that the bacterium is not a recent invader. Diverse lineages of B. burgdorferi have long existed in North America and the current Lyme disease epidemic is the result of ecological changes that have allowed deer, ticks and, finally, bacterium to invade.

The explosion of deer in the twentieth century into suburban landscapes, free of wolf predators and with strict hunting restrictions, allowed deer ticks to rapidly invade throughout much of New England and the Midwest. Climate change has also contributed. Warmer winters accelerate ticks’ life cycles and allow them to survive an estimated 28 miles further north each year.

Ticks expanded into suburbanized landscapes—full of animals like white-footed mice and robins, excellent hosts for B. burgdorferi. The expansion of ticks into habitats with ideal hosts allowed the bacterium to spread.

Adalgisa Caccone, a lecturer at Yale in Ecology and Evolutionary Biology and a senior research scientist at the School of Public Health, and Maria Diuk-Wasser, of the Department of Ecology, Evolutionary and Environmental Biology at Columbia University, are senior authors. Giovanna Carpi, of the Johns Hopkins School of Medicine, also contributed to the research.

How &aposConvalescent Plasma&apos Treatment Works

Nobel Prize winning German bacteriologist and physiologist Emil Adolf von Behring, right, uses a syringe to inject a guinea pig held by lab assistant, circa 1890.

Stock Montage/Getty Images

Von Behring’s antitoxin wasn’t a vaccine, but the earliest example of a treatment method called 𠇌onvalescent plasma” that’s being resurrected as a potential treatment for COVID-19. Convalescent plasma is blood plasma extracted from an animal or human patient who has 𠇌onvalesced” or recovered from infection with a particular disease.

𠇌onvalescent plasma has been used throughout history when confronting an infectious disease where you have people who recover and there’s no other therapy available,” says Warner Greene, director of the Center for HIV Cure Research at the Gladstone Institutes. “There must be something in their plasma—i.e. an antibody—that helped them recover.”

Convalescent plasma interacts differently with the immune system than a vaccine. When a person is treated with a vaccine, their immune system actively produces its own antibodies that will kill off any future encounters with the target pathogen. That’s called active immunity.

Convalescent plasma offers what’s called “passive immunity.” The body doesn’t create its own antibodies, but instead 𠇋orrows” them from another person or animal who has successfully fought off the disease. Unlike a vaccine, the protection doesn’t last a lifetime, but the borrowed antibodies can greatly reduce recovery times and even be the difference-maker between life and death.

𠇌onvalescent plasma is the crudest of the immunotherapies, but it can be effective,” says Greene.

Where did viruses come from?

Tracing the origins of viruses is difficult because they don't leave fossils and because of the tricks they use to make copies of themselves within the cells they've invaded. Some viruses even have the ability to stitch their own genes into those of the cells they infect, which means studying their ancestry requires untangling it from the history of their hosts and other organisms. What makes the process even more complicated is that viruses don't just infect humans they can infect basically any organism&mdashfrom bacteria to horses seaweed to people.

Still, scientists have been able to piece together some viral histories, based on the fact that the genes of many viruses&mdashsuch as those that cause herpes and mono&mdashseem to share some properties with cells' own genes. This could suggest that they started as big bits of cellular DNA and then became independent&mdashor that these viruses came along very early in evolution, and some of their DNA stuck around in cells' genomes. The fact that some viruses that infect humans share structural features with viruses that infect bacteria could mean that all of these viruses have a common origin, dating back several billion years. This highlights another problem with tracing virus origins: most modern viruses seem to be a patchwork of bits that come from different sources&mdasha sort of "mix and match" approach to building an organism.

The fact that viruses like the deadly Ebola and Marburg viruses, as well as the distantly related viruses that cause measles and rabies, are only found in a limited number of species suggests that those viruses are relatively new&mdashafter all, those organisms came along somewhat recently in evolutionary time. Many of these "new" viruses likely originated in insects many million years ago and at some point in evolution developed the ability to infect other species&mdashprobably as insects interacted with or fed from them.

HIV, which is thought to have first emerged in humans in the 1930s, is another kind of virus, known as a retrovirus. These simple viruses are akin to elements found in normal cells that have the ability to copy and insert themselves throughout the genome. There are a number of viruses that have a similar way of copying themselves&mdasha process that reverses the normal flow of information in cells, which is where the term "retro" comes from&mdashand their central machinery for replication may be a bridge from the original life-forms on this planet to what we know as life today. In fact, we carry among our genes many "fossilized" retroviruses&mdashleft over from the infection of distant ancestors&mdashwhich can help us trace our evolution as a species.

Then there are the viruses whose genomes are so large that scientists can't quite figure out what part of the cell they would have come from. Take, for instance, the largest-ever virus so far discovered, mimivirus: its genome is some 50 times larger than that of HIV and is larger than that of some bacteria. Some of the largest known viruses infect simple organisms such as amoebas and simple marine algae. This indicates that they may have an ancient origin, possibly as parasitic life-forms that then adapted to the "virus lifestyle." In fact, viruses may be responsible for significant episodes of evolutionary change, especially in more complex types of organisms.

At the end of the day, however, despite all of their common features and unique abilities to copy and spread their genomes, the origins of most viruses may remain forever obscure.

School Vaccine Rules Lead to Measles Elimination

“Public apathy in the face of infectious disease has always been a problem for public health,” Mooney says. The problem wasn’t the hesitancy seen today so much as complacency.

“It was a case of parents prioritizing getting food in their kids mouths than vaccinating them against measles,” particularly among poorer Americans, Mooney says. It cost parents about $10 ($82 today) to vaccinate one child against measles. The Vaccination Assistance Act in 1965 provided funds for measles immunization, but the money ran out in the 1970s, contributing to an upsurge in cases.

“Many mothers simply have not been educated about the benefits of and need for immunization,” noted the New York State Department of Health in 1971. That same year, Hilleman combined measles, mumps and rubella vaccines into the single MMR shot to cut down kids’ total jabs.

But it wasn’t until widespread school vaccination requirements and permanent federal funding that the country began inching toward measles elimination, finally achieved in 2000. (While cases of measles still crop up, the Centers for Disease Control defines elimination of a disease as the absence of continuous disease transmission for 12 months or more in a specific geographic area.)

“Relatively few people are alive now who witnessed epidemics of those diseases and their effects,” says Stanley Plotkin, the scientist who developed the rubella vaccine used in today’s MMR.

𠇊s somebody who practiced university pediatrics in the 1950s and 60s, I don’t take those diseases lightly at all.”

The history of measles: A scourge for centuries

Measles has been a scourge for centuries, afflicting millions of people. It has been blamed, in part, for decimating native populations of the Americas as Europeans explored the New World. In modern times, before a vaccine was developed, nearly every American contracted the virus, with its telltale skin blotches and fever. Measles was declared eradicated in the U.S. in 2000, but has staged a comeback as the inoculation rate has dropped. Here’s a history:

3rd to 10th century: Early physicians in Asia and North Africa identified and diagnosed measles, which was similar to smallpox, another highly contagious disease that triggered rashes and sores. Modern scientists would later suggest that measles evolved after the rise of early civilization in the Middle East and may have come from animals the virus was highly similar to rinderpest, which infected cattle.

In 340, Chinese alchemist Ko Hung described the difference between smallpox and measles a Christian priest, Ahrun, did the same in Egypt about 300 years later. In 910, the Persian physician Rhazes published the most widely celebrated early diagnoses of the two diseases.

1492: In a pattern that would be repeated across the world for centuries, Christopher Columbus and his fellow European explorers arrived in the Americas, bringing a raft of deadly diseases — including measles — with them.

Native Americans had no natural immunity to many of these diseases. Measles, smallpox, whooping cough, chicken pox, bubonic plague, typhus and malaria — already dangerous and often deadly in Europe — became even more efficient killers in the New World. By some estimates, the Native American population plunged by as much as 95% over the next 150 years due to disease.

1824-48: As was the case with many diseases, measles’ risk to Pacific Islanders was particularly dangerous in the 19th century as traders and travelers crisscrossed the globe. In 1824, Hawaii’s King Kamehameha II and Queen Kamamalu traveled to London to meet King George IV, but instead swiftly contracted measles. Both died within a month. The virus, along with several other diseases, struck Hawaii in 1848, killing up to a third of the native population.

1846: Danish physician Peter Ludwig Panum traveled to the Faroe Islands between Iceland and Norway to study a measles outbreak that had sickened more than 75% of the islands’ 7,782 residents — killing at least 102. Measles had not appeared on the isolated islands in decades, and Panum discovered that “not one” of the elderly residents who had been infected in 1781 “was attacked a second time.” Such immunity would later become key to defeating the virus. Panum observed measles’ contagiousness as it leaped from village to village.

1875: The HMS Dido brought measles to Fiji, killing 20,000 people — up to a third of the island’s natives. Measles outbreaks would continue to hopscotch Pacific islands for much of the next century.

1912: The United States required physicians to start reporting measles cases, which gave scientists a precise grasp of the disease’s widespread impact inside the country. Almost all Americans caught measles sometime in their life – mostly when young – and the outcome could be deadly. A study in the U.S. from 1912 to 1916 found 26 deaths for every 1,000 measles cases.

1954: Thomas C. Peebles, a World War II bomber pilot turned doctor, isolated the measles virus in an infected 11-year-old boy named David Edmonston. Peebles’ work paved the way for a vaccine.

1963: The first measles vaccines were licensed in the U.S.

Measles’ lethality had dropped by the 1960s, thanks to improved treatment and nutrition, with less than one death reported for every 1,000 cases. But before the vaccines, millions of American children were infected every year, and many developed serious side effects: An annual average of 48,000 measles patients required hospitalization, with 400 to 500 deaths per year, according to the Centers for Disease Control and Prevention. The most serious side effects included pneumonia and encephalitis – swelling of the brain. Hearing loss from measles-related ear infections was also common.

Measles vaccines slashed those infection rates. Over several decades, the vaccines were were bundled with vaccines for mumps and rubella into a booster shot parents now know as the MMR. State legislatures began mandating vaccination for school students in the 1960s and 1970s, and eventually every state and the District of Columbia adopted such laws, with some exemptions for medical, philosophical or religious reasons.

1989-91: A measles outbreak in the U.S. brought 55,000 cases, 11,000 hospitalizations and 123 deaths. The virus infected some vaccinated patients in the U.S., leading experts to begin recommending a second dose of MMR.

For the next decade, measles infection rates grew so low that, by 2000, measles was declared effectively eliminated in the U.S. But the virus remained prevalent around the world.

1998: A report in the British journal Lancet claimed a possible link between the measles vaccine and autism. Although the report was later debunked as fraudulent, its publication and a 1982 documentary called “DPT: Vaccine Roulette” aroused parents’ fears that vaccines might harm their children and spurred requests for vaccination exemptions.

The Lancet retracted that paper in 2010, and its author, Dr. Andrew Wakefield, lost his medical license. An investigation found that Wakefield had manipulated his data and altered patients’ medical histories to make his assertions more convincing.

“The MMR scare was based not on bad science but on a deliberate fraud,” Dr. Fiona Godlee, editor in chief of BMJ, formerly known as the British Medical Journal, wrote in 2011. Such “clear evidence of falsification of data should now close the door on this damaging vaccine scare.”

That did not happen, however. If anything, vaccination refusal rates continued to grow in some American communities. Scientists say at least 92% of a population must be vaccinated for so-called herd immunity to protect virtually everyone. As the vaccination percentage drops, the risk of outbreak rises.

2014: The worst American measles outbreak in two decades erupted, with more than 600 cases reported -- more than triple the 2013 total. One outbreak came in unvaccinated Amish communities in Ohio, where a missionary had traveled to the outbreak-ridden Philippines and returned home with the virus. Another outbreak came at Disneyland in December.

The Disneyland outbreak caused at least 52 of the 79 measles cases reported in California near the end of January, state officials said. By Jan. 31, a total of 102 measles cases had been reported in 14 states. At least two cases were reported in Mexico.

The Disneyland outbreak continues to draw scrutiny to anti-vaccination sentiments in California, where the rate of personal-belief vaccination exemptions at kindergartens with at least 10 students doubled to 3.1% in 2013 from 1.5% in 2007. That increase was driven largely by parents in wealthier school districts, many of which have fewer than 92% of kindergarteners immunized.

In the Santa Monica-Malibu Unified School District, for instance, nearly 15% of students last year were not vaccinated that number has now dropped to 11.5%, school officials say.

Measles continues to survive around the globe, causing 145,700 deaths in 2013, the World Health Organization says. Although the number of deaths have dropped by 75% between 2000 and 2013 because of vaccine use outside the U.S., the WHO says the virus remains “one of the leading causes of death among young children even though a safe and cost-effective vaccine is available.”

Rosanna Xia and Rong-Gong Lin II contributed to this report. Sources include: the Centers for Disease Control and Prevention “Smallpox and its Eradication,” the World Health Organization “The Columbian Exchange: A History of Disease, Food, and Ideas,” by Nathan Nunn and Nancy Qian. “Observations Made During The Epidemic Of Measles On The Faroe Islands In The Year 1846,” by Peter Ludwig Panum. “Measles Elimination in the United States,” the Journal of Infectious Diseases. “Diseased Goods: Global Exchanges in the Eastern Pacific Basin, 1770-1850,” by David Igler.

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Some HPV types, such as HPV-5, may establish infections that persist for the lifetime of the individual without ever manifesting any clinical symptoms. HPV types 1 and 2 can cause common warts in some infected individuals. [19] HPV types 6 and 11 can cause genital warts and laryngeal papillomatosis. [1]

Many HPV types are carcinogenic. [20] The table below lists common symptoms of HPV infection and the associated strains of HPV.

  • Highest risk: [21] 16, 18, 31, 45
  • Other high-risk: [21][23] 33, 35, 39, 51, 52, 56, 58, 59
  • Probably high-risk: [23] 26, 53, 66, 68, 73, 82

Warts Edit

Skin infection ("cutaneous" infection) with HPV is very widespread. [24] Skin infections with HPV can cause noncancerous skin growths called warts (verrucae). Warts are caused by a rapid growth of cells on the outer layer of the skin. [25] While cases of warts have been described since the time of ancient Greece, their viral cause was not known until 1907. [18]

Skin warts are most common in childhood and typically appear and regress spontaneously over the course of weeks to months. Recurring skin warts are common. [26] All HPVs are believed to be capable of establishing long-term "latent" infections in small numbers of stem cells present in the skin. Although these latent infections may never be fully eradicated, immunological control is thought to block the appearance of symptoms such as warts. Immunological control is HPV type-specific, meaning an individual may become resistant to one HPV type while remaining susceptible to other types. [ citation needed ]

    are usually found on the hands and feet, but can also occur in other areas, such as the elbows or knees. Common warts have a characteristic cauliflower-like surface and are typically slightly raised above the surrounding skin. Cutaneous HPV types can cause genital warts but are not associated with the development of cancer. are found on the soles of the feet they grow inward, generally causing pain when walking.
  • Subungual or periungual warts form under the fingernail (subungual), around the fingernail, or on the cuticle (periungual). They are more difficult to treat than warts in other locations. [27] are most commonly found on the arms, face, or forehead. Like common warts, flat warts occur most frequently in children and teens. In people with normal immune function, flat warts are not associated with the development of cancer. [28]

Common, flat, and plantar warts are much less likely to spread from person to person.

Genital warts Edit

HPV infection of the skin in the genital area is the most common sexually transmitted infection worldwide. [29] Such infections are associated with genital or anal warts (medically known as condylomata acuminata or venereal warts), and these warts are the most easily recognized sign of genital HPV infection. [ citation needed ]

The strains of HPV that can cause genital warts are usually different from those that cause warts on other parts of the body, such as the hands or feet, or even the inner thighs. A wide variety of HPV types can cause genital warts, but types 6 and 11 together account for about 90% of all cases. [30] [31] However, in total more than 40 types of HPV are transmitted through sexual contact and can infect the skin of the anus and genitals. [4] Such infections may cause genital warts, although they may also remain asymptomatic. [ citation needed ]

The great majority of genital HPV infections never cause any overt symptoms and are cleared by the immune system in a matter of months. Moreover, people may transmit the virus to others even if they do not display overt symptoms of infection. Most people acquire genital HPV infections at some point in their lives, and about 10% of women are currently infected. [29] A large increase in the incidence of genital HPV infection occurs at the age when individuals begin to engage in sexual activity. As with cutaneous HPVs, immunity to genital HPV is believed to be specific to a specific strain of HPV. [ citation needed ]

Laryngeal papillomatosis Edit

In addition to genital warts, infection by HPV types 6 and 11 can cause a rare condition known as recurrent laryngeal papillomatosis, in which warts form on the larynx [32] or other areas of the respiratory tract. [33] [34] These warts can recur frequently, may interfere with breathing, and in extremely rare cases can progress to cancer. For these reasons, repeated surgery to remove the warts may be advisable. [33] [35]

Cancer Edit

Virus types Edit

About a dozen HPV types (including types 16, 18, 31, and 45) are called "high-risk" types because persistent infection has been linked to cancer of the oropharynx, [3] larynx, [3] vulva, vagina, cervix, penis, and anus. [37] [38] These cancers all involve sexually transmitted infection of HPV to the stratified epithelial tissue. [1] [2] [36] Individuals infected with both HPV and HIV have an increased risk of developing cervical or anal cancer. [37] HPV type 16 is the strain most likely to cause cancer and is present in about 47% of all cervical cancers, [39] [40] and in many vaginal and vulvar cancers, [41] penile cancers, anal cancers, and cancers of the head and neck. [42]

Case statistics Edit

An estimated 561,200 new cancer cases worldwide (5.2% of all new cancers) were attributable to HPV in 2002, making HPV one of the most important infectious causes of cancer. [36] HPV-associated cancers make up over 5% of total diagnosed cancer cases worldwide, and this incidence is higher in developing countries where it is estimated to cause almost half a million cases each year. [36]

In the United States, about 30,700 cases of cancer due to HPV occur each year. [17]

The number of HPV-associated cancers in the period of 2008–2012 in the US. [17]
Cancer area Average annual number of cases HPV attributable (estimated) HPV 16/18 attributable (estimated)
Cervix 11,771 10,700 7,800
Oropharynx (men) 12,638 9,100 8,000
Oropharynx (women) 3,100 2,000 1,600
Vulva 3,554 2,400 1,700
Anus (women) 3,260 3,000 2,600
Anus (men) 1,750 1,600 1,400
Penis 1,168 700 600
Vagina 802 600 400
Rectum (women) 513 500 400
Rectum (men) 237 200 200
Total 38,793 30,700 24,600

Cancer development Edit

In some infected individuals, their immune systems may fail to control HPV. Lingering infection with high-risk HPV types, such as types 16, 18, 31, and 45, can favor the development of cancer. [43] Co-factors such as cigarette smoke can also enhance the risk of such HPV-related cancers. [44] [45]

HPV is believed to cause cancer by integrating its genome into nuclear DNA. Some of the early genes expressed by HPV, such as E6 and E7, act as oncogenes that promote tumor growth and malignant transformation. [18] HPV genome integration can also cause carcinogenesis by promoting genomic instability associated with alterations in DNA copy number. [46]

E6 produces a protein (also called E6) that binds to and inactivates a protein in the host cell called p53. Normally, p53 acts to prevent cell growth, and promotes cell death in the presence of DNA damage. p53 also upregulates the p21 protein, which blocks the formation of the cyclin D/Cdk4 complex, thereby preventing the phosphorylation of RB, and in turn, halting cell cycle progression by preventing the activation of E2F. In short, p53 is a tumor-suppressor protein that arrests the cell cycle and prevents cell growth and survival when DNA damage occurs. Thus, inactivation of p53 by E6 can promote unregulated cell division, cell growth, and cell survival, characteristics of cancer. [ citation needed ]

E6 also has a close relationship with the cellular protein E6-associated protein (E6-AP), which is involved in the ubiquitin ligase pathway, a system that acts to degrade proteins. E6-AP binds ubiquitin to the p53 protein, thereby flagging it for proteosomal degradation. [ citation needed ]

Squamous cell carcinoma of the skin Edit

Studies have also shown a link between a wide range of HPV types and squamous cell carcinoma of the skin. In such cases, in vitro studies suggest that the E6 protein of the HPV virus may inhibit apoptosis induced by ultraviolet light. [47]

Cervical cancer Edit

Nearly all cases of cervical cancer are associated with HPV infection, with two types, HPV16 and HPV18, present in 70% of cases. [1] [7] [39] [48] [49] [50] In 2012, twelve HPV types were considered carcinogenic for cervical cancer by the International Agency for Research on Cancer: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59. [51] HPV is necessary for cervical cancer to occur. [52] Persistent HPV infection increases the risk for developing cervical carcinoma. Individuals who have an increased incidence of these types of infection are women with HIV/AIDS, who are at a 22-fold increased risk of cervical cancer. [53] [54]

The carcinogenic HPV types in cervical cancer belong to the alphapapillomavirus genus and can be grouped further into HPV clades. [55] The two major carcinogenic HPV clades, alphapapillomavirus-9 (A9) and alphapapillomavirus-7 (A7), contain HPV16 and HPV18, respectively. [56] These two HPV clades were shown to have different effects on tumour molecular characteristics and patient prognosis, with clade A7 being associated with more aggressive pathways and an inferior prognosis. [57]

In 2012, about 528,000 new cases and 266,000 deaths from cervical cancer occurred worldwide. [29] Around 85% of these occurred in the developing world. [1]

Most HPV infections of the cervix are cleared rapidly by the immune system and do not progress to cervical cancer (see below the Clearance subsection in Virology). Because the process of transforming normal cervical cells into cancerous ones is slow, cancer occurs in people having been infected with HPV for a long time, usually over a decade or more (persistent infection). [33] [58]

Non-European (NE) HPV16 variants are significantly more carcinogenic than European (E) HPV16 variants. [59]

Anal cancer Edit

Studies show a link between HPV infection and anal cancers. Sexually transmitted HPVs are found in a large percentage of anal cancers. [36] Moreover, the risk for anal cancer is 17 to 31 times higher among HIV-positive individuals who were coinfected with high-risk HPV, and 80 times higher for particularly HIV-positive men who have sex with men. [60]

Anal Pap smear screening for anal cancer might benefit some subpopulations of men or women engaging in anal sex. [61] No consensus exists, though, that such screening is beneficial, or who should get an anal Pap smear. [62] [63]

Penile cancer Edit

HPV is associated with approximately 50% of penile cancers. In the United States, penile cancer accounts for about 0.5% of all cancer cases in men. HPV16 is the most commonly associated type detected. The risk of penile cancer increases 2- to 3-fold for individuals who are infected with HIV as well as HPV. [60]

Head and neck cancers Edit

Oral infection with high-risk carcinogenic HPV types (most commonly HPV 16) [17] is associated with an increasing number of head and neck cancers. [64] [49] [65] [66] This association is independent of tobacco and alcohol use. [66] [67] [68]

Sexually transmitted forms of HPV account for about 25% of cancers of the mouth and upper throat (the oropharynx) worldwide, [36] but the local percentage varies widely, from 70% in the United States [69] to 4% in Brazil. [70] Engaging in anal or oral sex with an HPV-infected partner may increase the risk of developing these types of cancers. [65]

In the United States, the number of newly diagnosed, HPV-associated head and neck cancers has surpassed that of cervical cancer cases. [64] The rate of such cancers has increased from an estimated 0.8 cases per 100,000 people in 1988 [71] to 4.5 per 100,000 in 2012, [17] and, as of 2015, the rate has continued to increase. [64] Researchers explain these recent data by an increase in oral sex. This type of cancer is more common in men than in women. [72]

The mutational profile of HPV-positive and HPV-negative head and neck cancer has been reported, further demonstrating that they are fundamentally distinct diseases. [73]

Lung cancer Edit

Some evidence links HPV to benign and malignant tumors of the upper respiratory tract. The International Agency for Research on Cancer has found that people with lung cancer were significantly more likely to have several high-risk forms of HPV antibodies compared to those who did not have lung cancer. [74] Researchers looking for HPV among 1,633 lung cancer patients and 2,729 people without the lung disease found that people with lung cancer had more types of HPV than noncancer patients did, and among lung cancer patients, the chances of having eight types of serious HPV were significantly increased. [75] In addition, expression of HPV structural proteins by immunohistochemistry and in vitro studies suggest HPV presence in bronchial cancer and its precursor lesions. [76] Another study detected HPV in the EBC, bronchial brushing and neoplastic lung tissue of cases, and found a presence of an HPV infection in 16.4% of the subjects affected by nonsmall cell lung cancer, but in none of the controls. [77] The reported average frequencies of HPV in lung cancers were 17% and 15% in Europe and the Americas, respectively, and the mean number of HPV in Asian lung cancer samples was 35.7%, with a considerable heterogeneity between certain countries and regions. [78]

Skin cancer Edit

In very rare cases, HPV may cause epidermodysplasia verruciformis (EV) in individuals with a weakened immune system. The virus, unchecked by the immune system, causes the overproduction of keratin by skin cells, resulting in lesions resembling warts or cutaneous horns which can ultimately transform into skin cancer, but the development is not well understood. [79] [80] The specific types of HPV that are associated with EV are HPV5, HPV8, and HPV14. [80]

Transmission Edit

Sexually transmitted HPV is divided into two categories: low-risk and high-risk. Low-risk HPVs cause warts on or around the genitals. Type 6 and 11 cause 90% of all genital warts and recurrent respiratory papillomatosis that causes benign tumors in the air passages. High-risk HPVs cause cancer and consist of about a dozen identified types. Type 16 and 18 are two that are responsible for causing most of HPV-caused cancers. These high-risk HPVs cause 5% of the cancers in the world. In the United States, high-risk HPVs cause 3% of all cancer cases in women and 2% in men. [81]

Risk factors for persistent genital HPV infections, which increases the risk for developing cancer, include early age of first sexual intercourse, multiple partners, smoking, and immunosuppression. [1] Genital HPV is spread by sustained direct skin-to-skin contact, with vaginal, anal, and oral sex being the most common methods. [4] [37] Occasionally it can spread from a mother to her baby during pregnancy. HPV is difficult to remove via standard hospital disinfection techniques, and may be transmitted in a healthcare setting on re-usable gynecological equipment, such as vaginal ultrasound transducers. [82] The period of communicability is still unknown, but probably at least as long as visible HPV lesions persist. HPV may still be transmitted even after lesions are treated and no longer visible or present. [83]

Perinatal Edit

Although genital HPV types can be transmitted from mother to child during birth, the appearance of genital HPV-related diseases in newborns is rare. However, the lack of appearance does not rule out asymptomatic latent infection, as the virus has proven to be capable of hiding for decades. Perinatal transmission of HPV types 6 and 11 can result in the development of juvenile-onset recurrent respiratory papillomatosis (JORRP). JORRP is very rare, with rates of about 2 cases per 100,000 children in the United States. [33] Although JORRP rates are substantially higher if a woman presents with genital warts at the time of giving birth, the risk of JORRP in such cases is still less than 1%. [ citation needed ]

Genital infections Edit

Genital HPV infections are transmitted primarily by contact with the genitals, anus, or mouth of an infected sexual partner. [84]

Of the 120 known human papilloma viruses, 51 species and three subtypes infect the genital mucosa. [85] Fifteen are classified as high-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82), three as probable high-risk (26, 53, and 66), and twelve as low-risk (6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, and 89). [20]

Condoms do not completely protect from the virus because the areas around the genitals including the inner thigh area are not covered, thus exposing these areas to the infected person's skin. [86]

Hands Edit

Studies have shown HPV transmission between hands and genitals of the same person and sexual partners. Hernandez tested the genitals and dominant hand of each person in twenty-five heterosexual couples every other month for an average of seven months. She found two couples where the man's genitals infected the woman's hand with high-risk HPV, two where her hand infected his genitals, one where her genitals infected his hand, two each where he infected his own hand, and she infected her own hand. [87] [88] Hands were not the main source of transmission in these twenty-five couples, but they were significant. [ citation needed ]

Partridge reports men's fingertips became positive for high risk HPV at more than half the rate (26% per two years) as their genitals (48%). [89] Winer reports 14% of fingertip samples from sexually active women were positive. [90]

Non-sexual hand contact seems to have little or no role in HPV transmission. Winer found all fourteen fingertip samples from virgin women negative at the start of her fingertip study. [90] In a separate report on genital HPV infection, 1% of virgin women (1 of 76) with no sexual contact tested positive for HPV, while 10% of virgin women reporting non-penetrative sexual contact were positive (7 of 72). [91]

Shared objects Edit

Sharing of possibly contaminated objects, for example, razors, [83] may transmit HPV. [92] [93] [94] Although possible, transmission by routes other than sexual intercourse is less common for female genital HPV infection. [84] Fingers-genital contact is a possible way of transmission but unlikely to be a significant source. [90] [95]

Blood Edit

Though it has traditionally been assumed that HPV is not transmissible via blood—as it is thought to only infect cutaneous and mucosal tissues—recent studies have called this notion into question. Historically, HPV DNA has been detected in the blood of cervical cancer patients. [96] In 2005, a group reported that, in frozen blood samples of 57 sexually naive pediatric patients who had vertical or transfusion-acquired HIV infection, 8 (14.0%) of these samples also tested positive for HPV-16. [97] This seems to indicate that it may be possible for HPV to be transmitted via blood transfusion. However, as non-sexual transmission of HPV by other means is not uncommon, this could not be definitively proven. In 2009, a group tested Australian Red Cross blood samples from 180 healthy male donors for HPV, and subsequently found DNA of one or more strains of the virus in 15 (8.3%) of the samples. [98] However, it is important to note that detecting the presence of HPV DNA in blood is not the same as detecting the virus itself in blood, and whether or not the virus itself can or does reside in blood in infected individuals is still unknown. As such, it remains to be determined whether HPV can or cannot be transmitted via blood. [96] This is of concern, as blood donations are not currently screened for HPV, and at least some organizations such as the American Red Cross and other Red Cross societies do not presently appear to disallow HPV-positive individuals from donating blood. [99]

Surgery Edit

Hospital transmission of HPV, especially to surgical staff, has been documented. Surgeons, including urologists and/or anyone in the room, is subject to HPV infection by inhalation of noxious viral particles during electrocautery or laser ablation of a condyloma (wart). [100] There has been a case report of a laser surgeon who developed extensive laryngeal papillomatosis after providing laser ablation to patients with anogenital condylomata. [100]

Virology Edit

HPV infection is limited to the basal cells of stratified epithelium, the only tissue in which they replicate. [102] The virus cannot bind to live tissue instead, it infects epithelial tissues through micro-abrasions or other epithelial trauma that exposes segments of the basement membrane. [102] The infectious process is slow, taking 12–24 hours for initiation of transcription. It is believed that involved antibodies play a major neutralizing role while the virions still reside on the basement membrane and cell surfaces. [102]

HPV lesions are thought to arise from the proliferation of infected basal keratinocytes. Infection typically occurs when basal cells in the host are exposed to the infectious virus through a disturbed epithelial barrier as would occur during sexual intercourse or after minor skin abrasions. HPV infections have not been shown to be cytolytic rather, viral particles are released as a result of degeneration of desquamating cells. HPV can survive for many months and at low temperatures without a host therefore, an individual with plantar warts can spread the virus by walking barefoot. [31]

HPV is a small double-stranded circular DNA virus with a genome of approximately 8000 base pairs. [37] [103] The HPV life cycle strictly follows the differentiation program of the host keratinocyte. It is thought that the HPV virion infects epithelial tissues through micro-abrasions, whereby the virion associates with putative receptors such as alpha integrins, laminins, and annexin A2 [104] leading to entry of the virions into basal epithelial cells through clathrin-mediated endocytosis and/or caveolin-mediated endocytosis depending on the type of HPV. [105] At this point, the viral genome is transported to the nucleus by unknown mechanisms and establishes itself at a copy number of 10-200 viral genomes per cell. A sophisticated transcriptional cascade then occurs as the host keratinocyte begins to divide and become increasingly differentiated in the upper layers of the epithelium. [ citation needed ]

The phylogeny of the various strains of HPV generally reflects the migration patterns of Homo sapiens and suggests that HPV may have diversified along with the human population. Studies suggest that HPV evolved along five major branches that reflect the ethnicity of human hosts, and diversified along with the human population. [106] Researchers have identified two major variants of HPV16, European (HPV16-E), and Non-European (HPV16-NE). [107]

E6/E7 proteins Edit

The two primary oncoproteins of high risk HPV types are E6 and E7. The “E” designation indicates that these two proteins are early proteins (expressed early in the HPV life cycle), while the "L" designation indicates that they are late proteins (late expression). [49] The HPV genome is composed of six early (E1, E2, E4, E5, E6, and E7) open reading frames (ORF), two late (L1 and L2) ORFs, and a non-coding long control region (LCR). [109] After the host cell is infected viral early promoter is activated and a polycistronic primary RNA containing all six early ORFs is transcribed. This polycistronic RNA then undergoes active RNA splicing to generate multiple isoforms of mRNAs. [110] One of the spliced isoform RNAs, E6*I, serves as an E7 mRNA to translate E7 protein. [111] However, viral early transcription subjects to viral E2 regulation and high E2 levels repress the transcription. HPV genomes integrate into host genome by disruption of E2 ORF, preventing E2 repression on E6 and E7. Thus, viral genome integration into host DNA genome increases E6 and E7 expression to promote cellular proliferation and the chance of malignancy. The degree to which E6 and E7 are expressed is correlated with the type of cervical lesion that can ultimately develop. [103]

The E6/E7 proteins inactivate two tumor suppressor proteins, p53 (inactivated by E6) and pRb (inactivated by E7). [112] The viral oncogenes E6 and E7 [113] are thought to modify the cell cycle so as to retain the differentiating host keratinocyte in a state that is favourable to the amplification of viral genome replication and consequent late gene expression. E6 in association with host E6-associated protein, which has ubiquitin ligase activity, acts to ubiquitinate p53, leading to its proteosomal degradation. E7 (in oncogenic HPVs) acts as the primary transforming protein. E7 competes for retinoblastoma protein (pRb) binding, freeing the transcription factor E2F to transactivate its targets, thus pushing the cell cycle forward. All HPV can induce transient proliferation, but only strains 16 and 18 can immortalize cell lines in vitro. It has also been shown that HPV 16 and 18 cannot immortalize primary rat cells alone there needs to be activation of the ras oncogene. In the upper layers of the host epithelium, the late genes L1 and L2 are transcribed/translated and serve as structural proteins that encapsidate the amplified viral genomes. Once the genome is encapsidated, the capsid appears to undergo a redox-dependent assembly/maturation event, which is tied to a natural redox gradient that spans both suprabasal and cornified epithelial tissue layers. This assembly/maturation event stabilizes virions, and increases their specific infectivity. [114] Virions can then be sloughed off in the dead squames of the host epithelium and the viral lifecycle continues. [115] A 2010 study has found that E6 and E7 are involved in beta-catenin nuclear accumulation and activation of Wnt signaling in HPV-induced cancers. [116]

Latency period Edit

Once an HPV virion invades a cell, an active infection occurs, and the virus can be transmitted. Several months to years may elapse before squamous intraepithelial lesions (SIL) develop and can be clinically detected. The time from active infection to clinically detectable disease may make it difficult for epidemiologists to establish which partner was the source of infection. [100]

Clearance Edit

Most HPV infections are cleared up by most people without medical action or consequences. The table provides data for high-risk types (i.e. the types found in cancers). [ citation needed ]

Clearance rates of high risk types of HPV [117]
Months after initial positive test 8 months 12 months 18 months
% of men tested negative 70% 80% 100%

Clearing an infection does not always create immunity if there is a new or continuing source of infection. Hernandez' 2005-6 study of 25 couples reports "A number of instances indicated apparent reinfection [from partner] after viral clearance." [87]

Over 170 types of HPV have been identified, and they are designated by numbers. [8] [112] They may be divided into "low-risk" and "high-risk" types. Low-risk types cause warts and high-risk types can cause lesions or cancer. [119] [120]

Cervical testing Edit

Guidelines from the American Cancer Society recommend different screening strategies for cervical cancer based on a woman's age, screening history, risk factors and choice of tests. [121] Because of the link between HPV and cervical cancer, the ACS currently recommends early detection of cervical cancer in average-risk asymptomatic adults primarily with cervical cytology by Pap smear, regardless of HPV vaccination status. Women aged 30–65 should preferably be tested every 5 years with both the HPV test and the Pap test. In other age groups, a Pap test alone can suffice unless they have been diagnosed with atypical squamous cells of undetermined significance (ASC-US). [122] Co-testing with a Pap test and HPV test is recommended because it decreases the rate of false-negatives. According to the National Cancer Institute, "The most common test detects DNA from several high-risk HPV types, but it cannot identify the types that are present. Another test is specific for DNA from HPV types 16 and 18, the two types that cause most HPV-associated cancers. A third test can detect DNA from several high-risk HPV types and can indicate whether HPV-16 or HPV-18 is present. A fourth test detects RNA from the most common high-risk HPV types. These tests can detect HPV infections before cell abnormalities are evident. [ citation needed ]

"Theoretically, the HPV DNA and RNA tests could be used to identify HPV infections in cells taken from any part of the body. However, the tests are approved by the FDA for only two indications: for follow-up testing of women who seem to have abnormal Pap test results and for cervical cancer screening in combination with a Pap test among women over age 30." [123]

Mouth testing Edit

Guidelines for oropharyngeal cancer screening by the Preventive Services Task Force and American Dental Association in the U.S. suggest conventional visual examination, but because some parts of the oropharynx are hard to see, this cancer is often only detected in later stages. [60]

The diagnosis of oropharyngeal cancer occurs by biopsy of exfoliated cells or tissues. The National Comprehensive Cancer Network and College of American Pathologists recommend testing for HPV in oropharyngeal cancer. [60] However, while testing is recommended, there is no specific type of test used to detect HPV from oral tumors that is currently recommended by the FDA in the United States. Because HPV type 16 is the most common type found in oropharyngeal cancer, p16 immunohistochemistry is one test option used to determine if HPV is present, [124] which can help determine course of treatment since tumors that are negative for p16 have better outcomes. Another option that has emerged as a reliable option is HPV DNA in situ hybridization (ISH) which allows for visualization of the HPV. [60]

Testing men Edit

There is not a wide range of tests available even though HPV is common most studies of HPV used tools and custom analysis not available to the general public. [125] [ needs update ] Clinicians often depend on the vaccine among young people and high clearance rates (see Clearance subsection in Virology) to create a low risk of disease and mortality, and treat the cancers when they appear. Others believe that reducing HPV infection in more men and women, even when it has no symptoms, is important (herd immunity) to prevent more cancers rather than just treating them. [126] [127] [ needs update ] Where tests are used, negative test results show safety from transmission, and positive test results show where shielding (condoms, gloves) is needed to prevent transmission until the infection clears. [128]

Studies have tested for and found HPV in men, including high-risk types (i.e. the types found in cancers), on fingers, mouth, saliva, anus, urethra, urine, semen, blood, scrotum and penis. [125]

The Qiagen/Digene kit mentioned in the previous section was used successfully off label to test the penis, scrotum and anus [129] of men in long-term relationships with women who were positive for high-risk HPV. 60% of them were found to carry the virus, primarily on the penis. [129] [ needs update ] Other studies used cytobrushes and custom analysis. [130] [131] [ needs update ]

In one study researchers sampled subjects' urethra, scrotum and penis. [130] [131] [ needs update ] Samples taken from the urethra added less than 1% to the HPV rate. Studies like this led Giuliano to recommend sampling the glans, shaft and crease between them, along with the scrotum, since sampling the urethra or anus added very little to the diagnosis. [89] Dunne recommends the glans, shaft, their crease, and the foreskin. [125]

In one study the subjects were asked not to wash their genitals for 12 hours before sampling, including the urethra as well as the scrotum and the penis. [130] Other studies are silent on washing - a particular gap in studies of the hands. [ citation needed ]

One small study used wet cytobrushes, rather than wet the skin. [131] It found a higher proportion of men to be HPV-positive when the skin was rubbed with a 600 grit emery paper before being swabbed with the brush, rather than swabbed with no preparation. It's unclear whether the emery paper collected the virions or simply loosened them for the swab to collect.

Studies have found self-collection (with emery paper and Dacron swabs) as effective as collection done by a clinician, and sometimes more so, since patients were more willing than a clinician to scrape vigorously. [132] [ needs update ] [133] Women had similar success in self-sampling using tampons, swabs, cytobrushes and lavage. [134] [ needs update ]

Several studies used cytobrushes to sample fingertips and under fingernails, without wetting the area or the brush. [90] [95] [135] [ needs update ]

Other studies analyzed urine, semen, and blood and found varying amounts of HPV, [125] but there is not a publicly available test for those yet.

Other testing Edit

Although it is possible to test for HPV DNA in other kinds of infections, [125] there are no FDA-approved tests for general screening in the United States [136] or tests approved by the Canadian government, [137] since the testing is inconclusive and considered medically unnecessary. [138]

Genital warts are the only visible sign of low-risk genital HPV and can be identified with a visual check. These visible growths, however, are the result of non-carcinogenic HPV types. Five percent acetic acid (vinegar) is used to identify both warts and squamous intraepithelial neoplasia (SIL) lesions with limited success [ citation needed ] by causing abnormal tissue to appear white, but most doctors have found this technique helpful only in moist areas, such as the female genital tract. [ citation needed ] At this time, HPV tests for males are used only in research. [ citation needed ]

Research into testing for HPV by antibody presence has been done. The approach is looking for an immune response in blood, which would contain antibodies for HPV if the patient is HPV positive. [139] [140] [141] [142] The reliability of such tests has not been proven, as there has not been a FDA approved product as of August 2018 [143] testing by blood would be a less invasive test for screening purposes.

The HPV vaccines can prevent the most common types of infection. [4] To be effective they must be used before an infection occurs and are therefore recommended between the ages of nine and thirteen. Cervical cancer screening, such as with the Papanicolaou test (pap) or looking at the cervix after using acetic acid, can detect early cancer or abnormal cells that may develop into cancer. This allows for early treatment which results in better outcomes. [1] Screening has reduced both the number and deaths from cervical cancer in the developed world. [15] Warts can be removed by freezing. [5]

Vaccines Edit

Three vaccines are available to prevent infection by some HPV types: Gardasil, Gardasil 9 and Cervarix all three protect against initial infection with HPV types 16 and 18, which cause most of the HPV-associated cancer cases. Gardasil also protects against HPV types 6 and 11, which cause 90% of genital warts. Gardasil is a recombinant quadrivalent vaccine, whereas Cervarix is bivalent, and is prepared from virus-like particles (VLP) of the L1 capsid protein. Gardasil 9 is nonavalent, it has the potential to prevent about 90% of cervical, vulvar, vaginal, and anal cancers. It can protect for HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 the latter five cause up to 20% of cervical cancers which were not previously covered. [144]

The vaccines provide little benefit to women already infected with HPV types 16 and 18. [145] For this reason, the vaccine is recommended primarily for those women not yet having been exposed to HPV during sex. The World Health Organization position paper on HPV vaccination clearly outlines appropriate, cost-effective strategies for using HPV vaccine in public sector programs. [146]

There is high-certainty evidence that HPV vaccines protect against precancerous cervical lesions in young women, particularly those vaccinated aged 15 to 26. [147] HPV vaccines do not increase the risk of serious adverse events. [147] Longer follow-up is needed to monitor the impact of HPV vaccines on cervical cancer. [147]

The CDC recommends the vaccines be delivered in two shots at an interval of least 6 months for those aged 11–12, and three doses for those 13 and older. [148] In most countries, they are funded only for female use, but are approved for male use in many countries, and funded for teenage boys in Australia. The vaccine does not have any therapeutic effect on existing HPV infections or cervical lesions. [149] In 2010, 49% of teenage girls in the US got the HPV vaccine. [ citation needed ]

Following studies suggesting that the vaccine is more effective in younger girls [150] than in older teenagers, the United Kingdom, Switzerland, Mexico, the Netherlands and Quebec began offering the vaccine in a two-dose schedule for girls aged under 15 in 2014. [ citation needed ]

Cervical cancer screening recommendations have not changed for females who receive HPV vaccine. It remains a recommendation that women continue cervical screening, such as Pap smear testing, even after receiving the vaccine, since it does not prevent all types of cervical cancer. [149] [151]

Both men and women are carriers of HPV. [152] The Gardasil vaccine also protects men against anal cancers and warts and genital warts. [153]

Duration of both vaccines' efficacy has been observed since they were first developed, and is expected to be longlasting. [154]

In December 2014, the FDA approved a nine-valent Gardasil-based vaccine, Gardasil 9, to protect against infection with the four strains of HPV covered by the first generation of Gardasil as well as five other strains responsible for 20% of cervical cancers (HPV-31, HPV-33, HPV-45, HPV-52, and HPV-58). [155]

Condoms Edit

The Centers for Disease Control and Prevention says that male "condom use may reduce the risk for genital human papillomavirus (HPV) infection" but provides a lesser degree of protection compared with other sexual transmitted diseases "because HPV also may be transmitted by exposure to areas (e.g., infected skin or mucosal surfaces) that are not covered or protected by the condom." [156]

Disinfection Edit

The virus is unusually hardy, and is immune to most common disinfectants. It is the first virus ever shown to be resistant to inactivation by glutaraldehyde, which is among the most common strong disinfectants used in hospitals. [157] Diluted sodium hypochlorite bleach is effective, [157] but cannot be used on some types of re-usable equipment, such as ultrasound transducers. [82] As a result of these difficulties, there is developing concern about the possibility of transmitting the virus on healthcare equipment, particularly reusable gynecological equipment that cannot be autoclaved. [158] [159] For such equipment, some health authorities encourage use of UV disinfection [160] or a non-hypochlorite "oxidizing‐based high‐level disinfectant [bleach] with label claims for non‐enveloped viruses", [161] such as a strong hydrogen peroxide solution [162] [160] or chlorine dioxide wipes. [160] Such disinfection methods are expected to be relatively effective against HPV. [ citation needed ]

There is currently no specific treatment for HPV infection. [163] [164] [165] However, the viral infection is usually cleared to undetectable levels by the immune system. [166] According to the Centers for Disease Control and Prevention, the body's immune system clears HPV naturally within two years for 90% of cases (see Clearance subsection in Virology for more detail). [163] However, experts do not agree on whether the virus is completely eliminated or reduced to undetectable levels, and it is difficult to know when it is contagious. [167] [ needs update ]

Follow up care is usually recommended and practiced by many health clinics. [168] Follow-up is sometimes not successful because a portion of those treated do not return to be evaluated. In addition to the normal methods of phone calls and mail, text messaging and email can improve the number of people who return for care. [169] As of 2015 it is unclear the best method of follow up following treatment of cervical intraepithelial neoplasia. [170]

Globally, 12% of women are positive for HPV DNA, with rates varying by age and country. [171] The highest rates of HPV are in younger women, with a rate of 24% in women under 25 years. [172] Rates decline in older age groups in Europe and the Americas, but less so in Africa and Asia. The rates are highest in Sub-Saharan Africa (24%) and Eastern Europe (21%) and lowest in North America (5%) and Western Asia (2%). [171]

The most common types of HPV worldwide are HPV16 (3.2%), HPV18 (1.4%), HPV52 (0.9%), HPV31 (0.8%), and HPV58 (0.7%). High-risk types of HPV are also distributed unevenly, with HPV16 having a rate around 13% in Africa and 30% in West and Central Asia. [172]

Like many diseases, HPV disproportionately affects low-income and resource-poor countries. The higher rates of HPV in Sub-Saharan Africa, for example, may be related to high exposure to human immunodeficiency virus (HIV) in the region. Other factors that impact the global spread of disease are sexual behaviors including age of sexual debut, number of sexual partners, and ease of access to barrier contraception, all of which vary globally. [171] [173]

United States Edit

HPV prevalence among women by age, including 20 low-risk types and 23 high-risk types [174]
Age (years) Prevalence (%)
14 to 19 24.5%
20 to 24 44.8%
25 to 29 27.4%
30 to 39 27.5%
40 to 49 25.2%
50 to 59 19.6%
14 to 59 26.8%

HPV is estimated to be the most common sexually transmitted infection in the United States. [174] Most sexually active men and women will probably acquire genital HPV infection at some point in their lives. [39] The American Social Health Association estimates that about 75–80% of sexually active Americans will be infected with HPV at some point in their lifetime. [175] [176] By the age of 50 more than 80% of American women will have contracted at least one strain of genital HPV. [174] [177] It was estimated that, in the year 2000, there were approximately 6.2 million new HPV infections among Americans aged 15–44 of these, an estimated 74% occurred to people between ages of 15 and 24. [178] Of the STDs studied, genital HPV was the most commonly acquired. [178] In the United States, it is estimated that 10% of the population has an active HPV infection, 4% has an infection that has caused cytological abnormalities, and an additional 1% has an infection causing genital warts. [179]

Estimates of HPV prevalence vary from 14% to more than 90%. [180] One reason for the difference is that some studies report women who currently have a detectable infection, while other studies report women who have ever had a detectable infection. [181] [182] Another cause of discrepancy is the difference in strains that were tested for. [ citation needed ]

One study found that, during 2003–2004, at any given time, 26.8% of women aged 14 to 59 were infected with at least one type of HPV. This was higher than previous estimates 15.2% were infected with one or more of the high-risk types that can cause cancer. [174] [183]

The prevalence for high-risk and low-risk types is roughly similar over time. [174]

Human papillomavirus is not included among the diseases that are typically reportable to the CDC as of 2011. [184] [185]

Ireland Edit

On average 538 cases of HPV-associated cancers were diagnosed per year in Ireland during the period 2010 to 2014. [186] Cervical cancer was the most frequent HPV-associated cancer with on average 292 cases per year (74% of the female total, and 54% of the overall total of HPV-associated cancers). [186] A study of 996 cervical cytology samples in an Irish urban female, opportunistically screened population, found an overall HPV prevalence of 19.8%, HPV 16 at 20% and HPV 18 at 12% were the commonest high-risk types detected. In Europe, types 16 and 18 are responsible for over 70% of cervical cancers. [187] Overall rates of HPV-associated invasive cancers may be increasing. Between 1994 and 2014, there was a 2% increase in the rate of HPV-associated invasive cancers per year for both sexes in Ireland. [186]

As HPV is known to be associated with ano-genital warts, these are notifiable to the Health Protection Surveillance Centre (HPSC). Genital warts are the second most common STI in Ireland. [188] There were 1,281 cases of ano-genital warts notified in 2017, which was a decrease on the 2016 figure of 1,593. [189] The highest age-specific rate for both male and female was in the 25-29 year old age range, 53% of cases were among males. [189]

Sri Lanka Edit

In Sri Lanka, the prevalence of HPV is 15.5% regardless of their cytological abnormalities. [190]

In 1972, the association of the human papillomaviruses with skin cancer in epidermodysplasia verruciformis was proposed by Stefania Jabłońska in Poland. In 1978, Jabłońska and Gerard Orth at the Pasteur Institute discovered HPV-5 in skin cancer. [191] In 1976 Harald zur Hausen published the hypothesis that human papilloma virus plays an important role in the cause of cervical cancer. In 1983 and 1984 zur Hausen and his collaborators identified HPV16 and HPV18 in cervical cancer. [192]

The HeLa cell line contains extra DNA in its genome that originated from HPV type 18. [193]

The Ludwig-McGill HPV Cohort is one of the world's largest longitudinal studies of the natural history of human papillomavirus (HPV) infection and cervical cancer risk. It was established in 1993 by Ludwig Cancer Research and McGill University in Montreal, Canada. [ citation needed ]

Research into origins of measles provides insight for dealing with current, future pandemics

A complex research project designed to answer basic questions about how the human measles virus diverged from a related cattle pathogen has revealed the divergence may have occurred as early as the 6th century BCE, a time where cities were growing and interconnecting, through trade, travel, and war, across Eurasia from China to the Mediterranean.

One of the co-leaders of the project is Dr. Marc Suchard, MD, PhD, professor of Biostatistics, Biomathematics, & Human Genetics at the UCLA Fielding School of Public Health, whose work served as the basis to reassess the divergence date of measles and the related rinderpest viruses. This period – 600 to 501 BCE – marks the earliest possible emergence of the measles virus and was estimated using advanced molecular clock modeling.

“Using computational approaches, we can now account for changing evolutionary dynamics over time. This showed that previous research had substantially underestimated the origin of the measles to the medieval times," said Suchard, who along with colleagues at KU Leuven in Belgium, developed these new models aimed at avoiding such biases.

“Measles appears to have arisen alongside the growth of large and, for the first time, inter-connected cities, which can be directly compared to the situation we face today in regard to emerging infectious diseases, like COVID-19, that arise from zoonotic pathogens,” Suchard said. “Travel between these urban areas took months or years when measles first appeared, but now it takes only hours or day – so we have similar health concerns, but vastly different time-scales.”

The study, published in Science on June 19th, summarizes research from scientists at the Robert Koch Institute (Germany), the KU Leuven (Belgium), the Berlin Museum of Medical History at the Charité (Germany), the University of Oklahoma, and the University of California, Los Angeles (UCLA)

Measles is a highly contagious infectious disease, which despite being vaccine-preventable, still imposes a tremendous burden on human health. Like many human diseases, measles originated in animals. A spill-over of a cattle-infecting virus, the common ancestor to both measles virus and its closest relative rinderpest virus is understood as likely to have given rise to the disease. The timing and circumstances of this important host switch are still debated.

Scientists involved in the current study began by analyzing a formalin-fixed lung from a 2-year-old measles patient who died in 1912 in Berlin, found in the collection of the Berlin Museum of Medical History. The team succeeded in assembling almost the entire measles virus genome - notably, this is the oldest human-infecting RNA virus genome sequenced to date.

“We were thrilled to find that recovery of viral RNA from such an old specimen was possible and, actually, quite an easy thing to do. This opens new perspectives for the study of RNA virus evolution,” said Sébastien Calvignac-Spencer (Robert Koch Institute), whose team sequenced the genome. Thomas Schnalke, the head of the Berlin Museum of Medical History, added: “This underlines the outstanding value of medical specimen collections, which are not only historical but also molecular archives.”

In a second step, the 1912 genome, coupled with already available genomic data from additional measles strains and the related rinderpest and Peste des petits ruminants viruses, served as the basis to reassess the divergence date of measles and rinderpest viruses.

This date was estimated using advanced molecular clock modeling by the teams led by Suchard and Philippe Lemey (KU Leuven) the researchers found the new divergence estimate falls into the 6th century BCE, a period marked by growing populations and the rise of large cities both in Europe and Asia. Measles requires large, connected populations for undisrupted circulation, which likely did not exist prior to this period.

“Of course we cannot say for sure if measles emerged in humans shortly after divergence and if that was linked to demographic change, but it is certainly a plausible scenario that can no longer be excluded,” said Kyle Harper, a historian from the University of Oklahoma.


Similar research methods could reveal more about how and when zoonotic diseases – those that pass from animals to humans – emerged, including Covid-19.

The current global health pandemic is caused by the SARS-CoV-2 strain of coronavirus, which is thought to have been transmitted from bats to humans via an 'intermediary animal' in China.

Understanding the emergence and evolution of human pathogens plays a pivotal role in predicting the trajectories of outbreaks, according to scientists.

Many infectious diseases arose after the Stone Age revolution, when hunter gatherers turned to farming.

‘Although it is broadly accepted this also applies to measles, the exact date of emergence for this disease is controversial,’ said study author Dr Sebastien Calvignac-Spencer, an epidemiologist at the Robert Koch Institute in Berlin, whose research has published in Science.

A measles rash. Measles belongs to a group of diseases called morbilliviruses. They are found in various mammals - and are adept at jumping from one host species to another

Autopsy report for 1912 measles case archived by the Berlin Museum of Medical History of the Charité. To get a better fix on the origins of measles, researchers reconstructed the measles virus genome using lung samples collected from a 1912 measles case

Measles: a highly contagious disease

Measles belongs to a group of diseases called morbilliviruses.

They are found in various mammals - and are adept at jumping from one host species to another.

The common ancestor of measles was a virus that jumped into humans after cattle were domesticated.

It is known non-human morbilliviruses can easily adapt to enter human cells.

There are fears relatives of measles could jump from animals to us today.

Despite immunisation programmes incidence has recently been on the rise from 2017 compared with 2018.

In 2018 there were 9.8 million cases of measles and 142,000 deaths, according to estimates from the World Health Organisation (WHO) and the US Centers for Diseases Control and Prevention.

In 2017, there were 7.6 million cases of measles and 124,000 deaths.

‘The results paint a new portrait of the evolutionary history of the measles virus.

‘They support a scenario where a bovine virus ancestor circulated among cattle for thousands of years, before jumping to humans once settlements began to surge in size in the late first millennium BC.

‘Our analyses show the measles virus potentially arose as early as the sixth century BC, possibly coinciding with the rise of large cities.’

The earliest clear clinical description of measles is often attributed to the legendary Persian doctor Al-Razi, or Rhazes, who ran a hospital in Bagdhad in the tenth century AD.

‘But Rhazes was extremely familiar with all available medical literature at his time and made use of earlier sources,’ said Dr Calvignac-Spencer.

‘Indian medical texts possibly describe measles several centuries before Rhazes.’

The measles virus is a prime target for both health authorities and scientists seeking to define the evolutionary paths of common human pathogens.

Researchers had long suspected that the measles virus emerged when the now-eradicated ‘rinderpest’ virus – German for ‘cattle-plague’ – spilled over from cattle into human populations.

This was previously thought to have happened around the end of the ninth century AD.

To learn more on the origins of measles, Dr Calvignac-Spencer and colleagues reconstructed the measles virus genome using lung samples collected from a 1912 measles case, housed at the Berlin Museum of Medical History of the Charité.

Specimens in the basement of the museum in Berlin, which features a variety of special exhibitions on medical science and history

The lung specimen encased in formaldehyde, also known as formalin, to preserve the proteins and vital structures within the tissue

They then compared sequencing data to a 1960 measles genome, 127 modern measles genomes and genomes from rinderpest and another cattle virus named PPRV.

Using a series of evolutionary and molecular clock models, the researchers traced the emergence of measles in humans between the years 1,174 BC and 165 BC, with a mean estimate of 528 BC.

The authors speculate a scenario where a bovine virus ancestor circulated among cattle for thousands of years, before jumping to humans once settlements began to surge in size in the late first millennium BC.

Virologists Professor Simon Ho of the University of Sydney and Dr Sebastian Duchene of the University of Melbourne, who were not involved in the study, said the research could better explain how pathogens jump from animals to humans.

Researchers at the Chinese Academy of Sciences, the People's Liberation Army and Institut Pasteur of Shanghai came to the conclusion that SARS-CoV-2 (pictured) may have come from bats

‘Dating analyses of pathogens have come under the spotlight in the ongoing pandemic,’ they write in an accompanying piece in Science.

‘Further genomic data from historical and ancient samples, along with more comprehensive and intensive surveys of viruses harboured in wildlife, will lead to continued refinements of the time scales of emergence and evolution of human pathogens.

‘In turn, these refinements will improve our understanding of the circumstances under which pathogens emerge in their hosts and the mechanisms by which they do so.’

Since the emergence of SARS-CoV-2 in Wuhan, China late last year there’s been much uncertainty surrounding the virus’s origin.

A previous report from scientists said the virus is 96 per cent identical to one found in bats, although this is yet to be officially confirmed as the source.

While it was initially assumed that the virus passed to humans in a Wuhan wet market, more recent studies have pointed to an anteater-like animal called a pangolin being the intermediary animal.

Pangolins are consumed as food in China and are also used in traditional medicine.

Professor Ho said the human SARS-CoV-2 virus split from its closest known relative – another coronavirus from a horseshoe bat – about 30 to 40 years ago, but the jump to humans most likely happened more recently.

‘Had the coronavirus jumped from its animal host to a human much earlier than November or December last year, it probably would have been detected,’ he said.

Scientists in China believe SARS-CoV-2 came from bats

The human COVID-19 SARS-CoV-2 virus split from its closest known relative – another coronavirus from a horseshoe bat (pictured) – about 30 to 40 years ago, according to University of Sydney Professor Simon Hothe jump to humans most likely happened more recently

Researchers at the Chinese Academy of Sciences, the People's Liberation Army and Institut Pasteur of Shanghai came to the conclusion that the coronavirus may have come from bats.

In a statement, the team said: 'The Wuhan coronavirus' natural host could be bats… but between bats and humans there may be an unknown intermediate.

Research published in the Lancet also determined bats as the most probable original host of the virus after samples were taken from the lungs of nine patients in Wuhan.

The team suggested that bats passed the disease on to an 'intermediate' host which was at the Huanan seafood market in Wuhan before being passed on to the 'terminal host' — humans.

Authorities have pointed the blame on food markets in Wuhan, the Chinese city at the centre of the outbreak that scientists are scrambling to contain.

Rodents and bats among other animals are slaughtered and sold in traditional 'wet markets', which tourists flock to see the 'real' side of the country.

From Bats to Human Lungs, the Evolution of a Coronavirus

For thousands of years, a parasite with no name lived happily among horseshoe bats in southern China. The bats had evolved to the point that they did not notice they went about their nightly flights unbothered. One day, the parasite—an ancestor of the coronavirus, SARS-CoV-2—had an opportunity to expand its realm. Perhaps it was a pangolin, the scaly anteater, an endangered species that is a victim of incessant wildlife trafficking and sold, often secretly, in live-animal markets throughout Southeast Asia and China. Or not. The genetic pathway remains unclear. But to survive in a new species, whatever it was, the virus had to mutate dramatically. It might even have taken a segment of a different coronavirus strain that already inhabited its new host, and morphed into a hybrid—a better, stronger version of itself, a pathogenic Everyman capable of thriving in diverse species. More recently, the coronavirus found a new species: ours. Perhaps a weary traveller rubbed his eyes, or scratched his nose, or was anxiously, unconsciously, biting his fingernails. One tiny, invisible blob of virus. One human face. And here we are, battling a global pandemic.

The world’s confirmed cases (those with a positive lab test for COVID-19, the disease caused by SARS-CoV-2) doubled in seven days, from nearly two hundred and thirteen thousand, on March 19th, to four hundred and sixty-seven thousand, on March 26th. Nearly twenty-one thousand people have died. The United States now has more confirmed cases than any country on earth, with more than eighty thousand on March 26th. These numbers are a fraction of the real, unknown total in this country and around the world, and the numbers will keep going up. Scientists behind a new study, published earlier this month in the journal Science, have found that for every confirmed case there are likely five to ten more people in the community with an undetected infection. This will likely remain the case. “The testing is not near adequate,” one of the study’s authors, Jeffrey Shaman, an environmental-health sciences professor at Columbia University, said. Comments from emergency-room doctors have been circulating on social media like S.O.S. flares. One, from Daniele Macchini, a doctor in Bergamo, north of Milan, described the situation as a “tsunami that has overwhelmed us.”

Scientists first discovered that coronaviruses originate among bats following the outbreak of Severe Acute Respiratory Syndrome (SARS) in 2003. Jonathan Epstein, an epidemiologist at the EcoHealth Alliance in New York who studies zoonotic viruses—those that can jump from animals to people—was part of a research team that went hunting for the source in China’s Guangdong Province, where simultaneous SARS outbreaks had occurred, suggesting multiple spillovers from animals to people. At first, health officials believed palm civets, a mongoose-like species commonly eaten in parts of China, were responsible, as they were widely sold at markets connected to the SARS outbreak, and tested positive for the virus. But civets bred elsewhere in Guangdong had no antibodies for the virus, indicating that the market animals were only an intermediary, highly infectious host. Epstein and others suspected that bats, which are ubiquitous in the area’s rural, agricultural hills, and were, at the time, also sold from cages at Guangdong’s wet markets, might be the coronavirus’s natural reservoir.

The researchers travelled through the countryside, setting up field labs inside limestone caverns and taking swabs from dozens of bats through the night. After months of investigation, Epstein’s team discovered four species of horseshoe bats that carried coronaviruses similar to SARS, one of which carried a coronavirus that was, genetically, a more than ninety per cent match. “They were found in all of the locations where SARS clusters were happening,” he said.

After years of further bat surveillance, researchers eventually found the direct coronavirus antecedent to SARS, as well as hundreds of other coronaviruses circulating among some of the fourteen hundred bats species that live on six continents. Coronaviruses, and other virus families, it turns out, have been co-evolving with bats for the entire span of human civilization, and possibly much longer. As the coronavirus family grows, different strains simultaneously co-infect individual bats, turning their little bodies into virus blenders, creating new strains of every sort, some more powerful than others. This process happens without making bats sick—a phenomenon that scientists have linked to bats’ singular ability, among mammals, to fly. The feat takes a severe toll, such that their immune systems have evolved a better way to repair cell damage and to fight off viruses without provoking further inflammation. But when these viruses leap into a new species—whether a pangolin or a civet or a human—the result can be severe, sometimes deadly, sickness.

In 2013, Epstein’s main collaborator in China, Shi Zheng-Li, sequenced a coronavirus found in bats, which, in January, she discovered shares ninety-six per cent of its genome with SARS-CoV-2. The two viruses have a common ancestor that dates back thirty to fifty years, but the absence of a perfect match suggests that further mutation took place in other bat colonies, and then in an intermediate host. When forty-one severe cases of pneumonia were first announced in Wuhan, in December, many of them were connected to a wet market with a notorious wildlife section. Animals are stacked in cages—rabbits on top of civets on top of ferret-badgers. “That’s just a gravitational exchange of fecal matter and viruses,” Epstein said. Chinese authorities reported that they tested animals at the market—all of which came back negative—but they have not specified which animals they tested, information that is crucial for Epstein’s detective work. Authorities later found the virus in samples taken from the market’s tables and gutters. But, because not all of the first patients were tied to the market, nor were they connected to one another, Epstein said, “it raised the question of, well, perhaps those forty-one weren’t the first cases.”

Analyses of the SARS-CoV-2 genome indicate a single spillover event, meaning the virus jumped only once from an animal to a person, which makes it likely that the virus was circulating among people before December. Unless more information about the animals at the Wuhan market is released, the transmission chain may never be clear. There are, however, numerous possibilities. A bat hunter or a wildlife trafficker might have brought the virus to the market. Pangolins happen to carry a coronavirus, which they might have picked up from bats years ago, and which is, in one crucial part of its genome, virtually identical to SARS-CoV-2. But no one has yet found evidence that pangolins were at the Wuhan market, or even that venders there trafficked pangolins. “We’ve created circumstances in our world somehow that allows for these viruses, which would otherwise not be known to cause any problems, to get into human populations,” Mark Denison, the director of pediatric infectious diseases at Vanderbilt University Medical Center’s Institute for Infection, Immunology, and Inflammation, told me. “And this one happened to say, ‘I really like it here.’ ”

The new coronavirus is an elusive killer. Since people have never seen this strain before, there is much about it that remains a mystery. But, in just the past few weeks, genetic sleuthing, atomic-level imaging, computer modelling, and prior research on other types of coronaviruses, including SARS and MERS (Middle East Respiratory Syndrome), have helped researchers to quickly learn an extraordinary amount—particularly what might treat or eradicate it, through social-distancing measures, antiviral drugs, and, eventually, a vaccine. Since January, nearly eight hundred papers about the virus have been posted on BIORxiv, a preprint server for studies that have not yet been peer-reviewed. More than a thousand coronavirus genome sequences, from different cases around the world, have been shared in public databases. “It’s insane,” Kristian Andersen, a professor in the Department of Immunology and Microbiology at Scripps Research, told me. “Almost the entire scientific field is focussed on this virus now. We’re talking about a warlike situation.”

There are endless viruses in our midst, made either of RNA or DNA. DNA viruses, which exist in much greater abundance around the planet, are capable of causing systemic diseases that are endemic, latent, and persistent—like the herpes viruses (which includes chicken pox), hepatitis B, and the papilloma viruses that cause cancer. “DNA viruses are the ones that live with us and stay with us,” Denison said. “They’re lifelong.” Retroviruses, like H.I.V., have RNA in their genomes but behave like DNA viruses in the host. RNA viruses, on the other hand, have simpler structures and mutate rapidly. “Viruses mutate quickly, and they can retain advantageous traits,” Epstein told me. “A virus that’s more promiscuous, more generalist, that can inhabit and propagate in lots of other hosts ultimately has a better chance of surviving.” They also tend to cause epidemics—such as measles, Ebola, Zika, and a raft of respiratory infections, including influenza and coronaviruses. Paul Turner, a Rachel Carson professor of ecology and evolutionary biology at Yale University, told me, “They’re the ones that surprise us the most and do the most damage.”

Scientists discovered the coronavirus family in the nineteen-fifties, while peering through early electron microscopes at samples taken from chickens suffering from infectious bronchitis. The coronavirus’s RNA, its genetic code, is swathed in three different kinds of proteins, one of which decorates the virus’s surface with mushroom-like spikes, giving the virus the eponymous appearance of a crown. Scientists found other coronaviruses that caused disease in pigs and cows, and then, in the mid-nineteen-sixties, two more that caused a common cold in people. (Later, widespread screening identified two more human coronaviruses, responsible for colds.) These four common-cold viruses might have come, long ago, from animals, but they are now entirely human viruses, responsible for fifteen to thirty per cent of the seasonal colds in a given year. We are their natural reservoir, just as bats are the natural reservoir for hundreds of other coronaviruses. But, since they did not seem to cause severe disease, they were mostly ignored. In 2003, a conference for nidovirales (the taxonomic order under which coronaviruses fall) was nearly cancelled, due to lack of interest. Then SARS emerged, leaping from bats to civets to people. The conference sold out.

SARS is closely related to the new virus we currently face. Whereas common-cold coronaviruses tend to infect only the upper respiratory tract (mainly the nose and throat), making them highly contagious, SARS primarily infects the lower respiratory system (the lungs), and therefore causes a much more lethal disease, with a fatality rate of approximately ten per cent. (MERS, which emerged in Saudi Arabia, in 2012, and was transmitted from bats to camels to people, also caused severe disease in the lower respiratory system, with a thirty-seven per cent fatality rate.) SARS-CoV-2 behaves like a monstrous mutant hybrid of all the human coronaviruses that came before it. It can infect and replicate throughout our airways. “That’s why it is so bad,” Stanley Perlman, a professor of microbiology and immunology who has been studying coronaviruses for more than three decades, told me. “It has the lower-respiratory severity of SARS and MERS coronaviruses, and the transmissibility of cold coronaviruses.”

One reason that SARS-CoV-2 may be so versatile, and therefore so successful, has to do with its particular talent for binding and fusing with lung cells. All coronaviruses use their spike proteins to gain entry to human cells, through a complex, multistep process. First, if one imagines the spike’s mushroom shape, the cap acts like a molecular key, fitting into our cells’ locks. Scientists call these locks receptors. In SARS-CoV-2, the cap binds perfectly to a receptor called the ACE-2, which can be found in various parts of the human body, including the lungs and kidney cells. Coronaviruses attack the respiratory system because their ACE-2 receptors are so accessible to the outside world. “The virus just hops in,” Perlman told me, “whereas it’s not easy to get to the kidney.”

While the first SARS virus attached to the ACE-2 receptor, as well, SARS-CoV-2 binds to it ten times more efficiently, Kizzmekia Corbett, the scientific lead of the coronavirus program at the National Institutes of Health Vaccine Research Center, told me. “The binding is tighter, which could potentially mean that the beginning of the infection process is just more efficient.” SARS-CoV-2 also seems to have a unique ability, which SARS and MERS did not have, to use enzymes from our human tissue—including one, widely available in our bodies, named furin—to sever the spike protein’s cap from its stem. Only then can the stem fuse the virus membrane and the human-cell membrane together, allowing the virus to spit its RNA into the cell. According to Lisa Gralinski, an assistant professor in the Department of Epidemiology at the University of North Carolina at Chapel Hill, this supercharged ability to bind to the ACE-2 receptor, and to use human enzymes to activate fusion, “could aid a lot in the transmissibility of this new virus and in seeding infections at a higher level.”

Once a coronavirus enters a person—lodging itself in the upper respiratory system and hijacking the cell’s hardware—it rapidly replicates. When most RNA viruses replicate themselves in a host, the process is quick and dirty, as they have no proofreading mechanism. This can lead to frequent and random mutations. “But the vast majority of those mutations just kill the virus immediately,” Andersen told me. Unlike other RNA viruses, however, coronaviruses do have some capacity to check for errors when they replicate. “They have an enzyme that actually corrects mistakes,” Denison told me.

It was Denison’s lab at Vanderbilt that first confirmed, in experiments on live viruses, the existence of this enzyme, which makes coronaviruses, in a sense, cunning mutators. The viruses can remain stable in a host when there is no selective pressure to change, but rapidly evolve when necessary. Each time they leap into a new species, for example, they are able to hastily transform in order to survive in the new environment, with its new physiology and a new immune system to battle. Once the virus is spreading easily within a species, though, its attitude is, “I’m happy, I’m good, no need to change,” Denison said. That seems to be playing out now in humans as SARS-CoV-2 circles the globe, there are slight variations among its strains, but none of them seem to affect the virus’s behavior. “This is not a virus that is rapidly adapting. It’s like the best car in the Indy 500. It’s out in front and there is no obstacle in its path. So there is no benefit to changing that car.”

A virus replicates in order to shed from its host—through mucus, snot, phlegm, and even our breath—as soon as possible, in great quantities, so that it can keep spreading. The coronavirus happens to be a brilliant shedder. A preprint study by German researchers, published earlier this month, and one of the first outside China to examine data from patients diagnosed with COVID-19, found clear evidence that infected people shed the coronavirus at significant rates before they develop symptoms. In effect—possibly due to that supercharged ability to bind and fuse to our cells—the virus wears an invisibility cloak. Scientists recently estimated that undocumented cases of COVID-19, or infected people with mild symptoms, are fifty-five per cent as contagious as severe cases. Another study found that in more severe cases (requiring hospitalization), patients shed the virus from their respiratory tracts for as long as thirty-seven days.

Outside a host, in parasitical purgatory, a virus is inert, not quite alive, but not dead, either. A hundred million coronavirus particles could fit on the head of a pin—typically, thousands or tens of thousands are necessary to infect an animal or a person—and they might remain viable for long stretches. Researchers at the Virus Ecology Unit of Rocky Mountain Laboratories, in Montana, a facility connected to the National Institute of Allergy and Infectious Diseases, have found that the virus can linger on copper for four hours, on a piece of cardboard for twenty-four hours, and on plastic or stainless steel for as long as three days. They also found that the virus can survive, for three hours, floating through the air, transmitted by the tiny respiratory droplets an infected person exhales, sneezes, or coughs out. (Other research suggests the virus might be able to exist as an aerosol, but only in very limited conditions.) Most virus particles, though, seem to lose their virulency fairly quickly. The infection window is highest in the first ten minutes. Still, the risk of infection has turned many of us, understandably, into germophobes.

All a virus wants is an endless chain of hosts. Contagion is the evolutionary end goal. Based on experiments so far, researchers estimate that COVID-19 is slightly more communicable than the common flu and less communicable than the most highly infectious viruses, like measles, with which a single sick person can infect around twelve other people. There are likely coronavirus super-spreaders—people who, for whatever reason, are almost entirely asymptomatic but transmit the disease to many other people. But pinning down an exact infection rate, at this point, is an impossible task. “We tend to focus on these absolute numbers as telling us how worried we should be,” Denison said. “Look, it’s like flooding. You know, is it up to my knees or is it up to my chin? It doesn’t matter. I need to do something to try to make sure I’m not gonna drive my car into the flood.”

In many places, we already have driven into the flood. As hundreds of people die each day, hospitals are running out of supplies, beds, and ventilators. In these severe COVID-19 cases, according to scientists’ current understanding, the disease may have more to do with a haywire immune response to the virus than anything else. Because the virus can gain a foothold in our lower respiratory system while still wearing that invisibility cloak, it “basically beats the immune system to the punch and starts replicating too rapidly,” Perlman said. When the immune system finally does register its presence, it might go into overdrive, and send everything in its arsenal to attack, since it has no specific antibodies to fight these strange new invaders. “It’s like pouring gas on the fire,” Denison told me. The lung tissue swells and fills with fluid. Breathing is restricted, as is the exchange of oxygen. “The host immune response just gets triggered to such an extreme level, and then builds on itself and builds on itself until ultimately the body kind of goes into shock,” Gralinski said. It is almost like an autoimmune disease the immune system is attacking parts of the body that it should not.

This type of response might be why the elderly are, on the whole, more vulnerable to COVID-19, just as they were to the SARS outbreak in 2003. (In that outbreak, there were almost no deaths among children under the age of thirteen, and, when kids did get sick, the disease was, on average, milder than what affected adults.) When studying SARS in mice models, Denison told me that he has observed a phenomenon known as “immune senescence,” in which older mice no longer had the capacity to respond in a balanced way to a new virus their immune systems’ overreaction then caused even more severe disease. This occurred in some of the worst cases during the first SARS outbreak, too, Denison said, and explains why antiviral drugs may be significantly more helpful at the onset of illness, before the immune system has had a chance to wreak havoc.

In the last decade, Denison’s lab and collaborators at the University of North Carolina have been researching antiviral treatments to try to find something that worked not just against SARS and MERS but for a new coronavirus which, they knew, would inevitably arrive. Together, they did much of the early research into the drug now known as Remdesivir, which is currently in development by Gilead and in studies on infected patients, and another antiviral drug compound, known as NHC. Both drugs, in animal models, were able to bypass, avoid, or block the coronavirus’s proofreading function, which helped stop the virus from replicating successfully in the body. “They worked very effectively against all the coronaviruses that we’ve tested,” Denison told me.

Coronaviruses likely have that proofreading enzyme because they are huge—one of the largest RNA viruses in existence—and they need a mechanism that maintains such a long genome’s structure. From our perspective, the benefit of such a big genome, Andersen told me, “is that the more genes and protein products a virus has, the more opportunities we have to design specific treatments against them.” For instance, the virus’s unique ability to use the human enzyme furin offers promise for antiviral drugs that act as furin inhibitors.

COVID-19, while still new to us hosts, will continue to be responsible for widespread infection and death. But, Epstein said, “Over time, as viruses evolve with their natural habitats, they tend to cause less severe disease. And that is good for both the host and the virus.” The more virulent strains might burn out (which, however, means many more awful deaths), while the remaining hosts might build up some immunity. More immediately, and urgently, the virus’s stability—how much it is thriving among us right now, and mutating only minimally—bodes well for the performance of antiviral drugs and, eventually, a vaccine. If the growing number of mitigation measures—this unprecedented national and international shutdown—are held in place for enough time, the speed at which the virus is spreading should slow, giving hospitals and health workers some relief. “The virus is our teacher,” Denison told me. It has spent thousands of years evolving to get where it is. We’re now just rushing to catch up.

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