illustration of three figures in silhouette, 2 with a large virus in the chest; background text says 'human papillomavirus' and HPV

The Virus That Owns the World

By Maryalice Yakutchik • Illustration by Dung Hoang

Keerti Shah’s got nothing against the human papillomavirus.

The virologist bears no grudge against the virus that causes half a million cervical cancers worldwide every year and now is blamed for a rise in head and neck cancers so surprisingly sharp that it may presage an imminent epidemic among U.S. baby boomers.

Revered for his Zen-like attitude as well as a body of research that has spanned six decades and spawned stunning discoveries about HPV’s cancer-causing ways, Shah simply is not the type to harbor ill will. Not against anyone or anything. Not even a bug that currently infects about 79 million Americans and will infect, at some point in their lives, almost every sexually active person. Especially not a bug that’s so successfully infectious.

In fact, Shah respects HPV. Not in the arched-eyebrow way you would an archrival, but with a fondness that belies kinship. A mere genetic snippet, and therefore in need of others’ cells to live, HPV just wants to communicate bits of itself. Survival requires transmission, replication.

“The viruses are not devious,” says Shah, his contagious smile conveying empathy. Papillomaviruses, he explains, have co-existed quite peacefully with humans throughout time and relatively rarely do harm.

“They own this world as much as we do. Don’t you think?”

If anyone understands HPV, it’s Shah, DrPH ’63, MPH ’57. In addition to having written the chapter on papillomaviruses in the definitive text Fields Virology, Shah gets HPV on an altogether different level, master practitioner that he is of human-to-human transmission of knowledge. During his tenure at Hopkins—57 years and counting—his scientific notions have spread over decades and across continents as his protégés instruct students, and now their students teach successive generations of HPV experts, all of whom embody and expand on Shah’s vision.

The 84-year-old Shah has mentored and collaborated with a who’s who of HPV, from upstart investigators to Harald zur Hausen—he won the Nobel Prize in 2008 for his role in the discovery of human papillomaviruses causing cervical cancer.

Their quarry, HPV, is a sprawling family with 150-plus different virus types identified, about 40 of which are sexually transmitted. HPV causes warts; the harmless kind that kids commonly get on their hands, as well as the genital warts that annually afflict about 360,000 sexually active people in the U.S. HPV contains two oncogenes, E6 and E7, which disrupt cell cycle control and produce cancers. Still, only a few high-risk members of this mostly benign family ever do cause trouble. One (HPV16) alone accounts for 50 percent of all cervical cancers and most head and neck cancers.

Identifying HPV11 as the cause of laryngeal papilloma in 1982 was one of Shah’s early successes. His career is linked with all the major HPV milestones, the headiest of which is rendering cervical cancer preventable. In 1999, Shah proved that HPV is responsible for essentially 100 percent of cervical cancers in all parts of the world. It’s the only example of a major human cancer that has a single cause—a fact that led to the development of a preventive vaccine recommended for adolescents since 2006. A “completely effective vaccine,” Shah notes, albeit one that’s still too expensive for use in Asia, Latin America and Africa where most of the 500,000 new cases of cervical cancer occur each year, and 200,000 people die annually from the disease.

It’s Shah’s habit to slough off accolades and extend credit to colleagues whom he refers to—no matter whether they are grad students or Nobel laureates—by first and last names as well as courtesy titles: “Dr. Patti Gravitt,” for instance.

A Shah protégé, Gravitt, PhD ’02, MS, is now vice dean at Perdana University in Kuala Lumpur and an associate professor in Epidemiology at the Bloomberg School. She and Shah recently co-authored a study that makes the case for a new self-screening strategy in developing nations. They argue that millions of women worldwide who don’t get screened regularly would be able to detect cervical cancers early enough for treatment if this kind of strategy were in place. Ninety percent of those screened, Shah says, would know without ever leaving home that they are not at risk; 10 percent would know they need to go to a clinic for further evaluation.

This latest paper of Shah’s reveals an unrealized dream: “What would I still like to do?” he asks. “Implement an HPV-screening method in India (relying on leadership in that country) which shows this method is both reliable and possible.”

Shah’s great strength, Gravitt explains, is keeping his eye on the public health focus: “Everything he does is directed toward trying to make sure we don’t get distracted by some random detail. Everything comes back to: Does it matter? Does it save lives? A lot of the work we did together was to develop methods to better detect and screen for HPV; to build a better mousetrap. Keerti’s push now is to get people to use the mousetrap.”

Gravitt’s own push has been to prove the virus behaves differently than everybody has always assumed.

According to all the published literature, HPV clears completely in the overwhelming majority of individuals who never even know they were infected. After a year or two, the virus DNA is undetectable. The implication: It’s gone. Any subsequent HPV infections detected during a person’s lifetime are assumed to be newly acquired, and not reactivations of past infections.

Gravitt’s data tell a different story. She’s deconstructing what was a nice, clean, linear narrative, and mucking it up with a messy truth: HPV is controlled, not cleared. Though it may be completely undetectable, it’s not cleared.

If anyone can buck the scientific status quo, it’s Gravitt. Renowned for having developed the gold standard method for detecting and genotyping HPV, she learned firsthand from Shah that hard-won scientific truth trumps all.

Increasingly her studies reveal that latent but undetectable HPV is reactivating in the cohorts she’s studying: menopausal women who have been monogamous or sexually abstinent for decades, for instance. Menopause and aging may be vulnerable times, immunologically speaking, during which the probability of reactivation is increased, says Gravitt, “but we really need to do more research to confirm that.”

The issue is contentious. In addition to those in the clearance camp, there’s the dismissive camp: So what if one says controlled, and another says cleared? If one says reactivate, and another says reinfect? Isn’t this all just semantics, like one says po-tay-to, and another says po-tah-to?

“Well, no,” Gravitt insists. “It’s important to figure out whether the virus clears or is controlled. It makes a big difference in terms of disease risk in later life, and in terms of how you might prevent HPV-associated disease, particularly in older people.”

The distinction also carries psycho-social importance, explains Anne Rositch, PhD, MSPH, a postdoc working in Gravitt’s lab. Increasingly, clinicians are confronting middle-aged patients in long, monogamous marriages who, oddly enough, have acquired “new” HPV infections, she says. They’re asking her, How could that happen? What’s going on?

Plausible answers come from molecular epidemiology, a hybrid science involving population-based research at a molecular level. In the tradition of Shah, Gravitt and Rositch are bench scientists whose expertise is analyzing biological samples in the context of big and diverse cohorts of people.

If the accepted HPV story is accurate—that it’s acquired during sexual debut and clears  within two years then the prevalence of HPV infection in populations should not be associated with individuals’ cumulative lifetime sexual behavior, Gravitt explains. Rather, only with their recent sexual behavior. But that’s not what she is finding.

Gravitt published dogma-defying findings in the Journal of Infectious Diseases in December 2012, under the title, “A Cohort Effect of the Sexual Revolution May Be Masking an Increase in Papillomavirus Detection at Menopause in the United States.” The study indicates a greater prevalence of HPV infection in the population of menopausal women whose sexual debut was post–sexual revolution than those whose debut was pre–sexual revolution. When her team looked at newly detected HPV in this cohort, only 13 percent of infection was attributed to new sex partners, whereas 72 percent was attributed to having a higher number of lifetime partners. The takeaway: These infections probably weren’t new.

“As long as you are controlling these infections, your immediate risk of [cancer] is going to be low,” Gravitt explains. “But if menopause, or just getting old, increases HPV reactivation, then we need to look at what this means for screening these older women who came of age during the sexual revolution and are much more likely to reach menopause with latent HPV than the postmenopausal women we have screened in the past.”

It will be important to determine if the historical low risk of cancer in postmenopausal women will continue to hold steady as the baby boomers age, she adds, and to reexamine questions like when and under what conditions is it safe to stop routine screening.

Helping Gravitt stay on track as she dogs the undetectable is decades-old advice from Shah: “One of the frustrating things about being a scientist is you work very hard and it seems no one is paying attention. [As a young investigator] I had been complaining to Keerti—kind of like, ‘Woe is me. How is it that no one sees what I do? Do I have it wrong?’ And Keerti just looked at me, with the sweetest face, and said, ‘Patti. You talk too much and write too little.’

“To this day, whenever I get into that anxious state, which can be paralyzing, I just shut up and sit down and write out what I’m thinking. Because nobody will pay attention until it’s down on paper.”

These days, most of the attention-grabbing headlines associated with HPV have to do with the fact that head and neck cancer is rising dramatically, especially among men, and is now as common in the U.S. as cervical cancer is among women. Each accounts for about 10,000 new cases annually.

Shah protégé Maura Gillison, MD, PhD ’01, established herself early on as an intellectual leader in a new field that straddled epidemiology, oncology and otolaryngology. Now, she and her students continue to push the frontiers of that field.

She demonstrated that HPV infection causes a distinct molecular, clinical and pathological subset of head and neck squamous cell carcinomas. An individual’s HPV status is the single most important prognostic factor in terms of whether someone will die from the disease, she says, even more important than how far along cancer has progressed. HPV-positive status is a strong predictor of survival. In fact, about 75 percent of HPV-related head and neck cancers are curable compared to 25 percent related to smoking. Also, there’s growing evidence that HPV-associated head and neck cancers require less aggressive and invasive treatment than head and neck cancers not caused by HPV. Gillison’s latest data reveal that the proportion of oropharynx cancers that were HPV-positive in the U.S. rose dramatically in the past couple of decades, from 16 percent during 1984–1989 to 73 percent during 2000–2004.

It was during an “intense three-year mentorship” beginning in 1996 that Keerti Shah taught her about science—and life, says Gillison, now at The Ohio State University

She recalls Shah’s attempts to temper her exacting nature by reminding her that “sometimes the perfect is the enemy of the excellent.” He chided her for not taking time to celebrate successes—like when their team in 2000 published the first strong evidence that HPV causes head and neck cancer in humans.

At the time, Gillison shared a lab with Gravitt. Both shared their mentor’s passion for making public health impacts with scientific findings. On Gillison’s list to complete in the summer of 2003 was a case-control study designed to definitively prove that the same human papillomavirus that causes cervical cancer also causes tonsillar cancer. Enter Gypsyamber D’Souza, a grad student who, under Gillison’s tutelage, promptly published key research in the New England Journal of Medicine.

It served D’Souza well, training with successive generations of HPV heavyweights. (So too did growing up in a household where the discussion of sex was not taboo, she says.) D’Souza, PhD ’06,

MPH, is focusing on HPV in high-risk groups, namely young adults, HIV-infected individuals, and men having sex with men. By studying patients with the disease and exploring infection in high-risk populations, the associate professor in Epidemiology aims to find out why infection leads to disease in some people but not others.

Her research necessitates a candor and nonchalance about conditions and behaviors, which some clinicians—especially those whose expertise is confined to the head and neck—might find hard to broach with patients. Although dentists generally perform quick look-see exams for cancer, HPV-related oropharynx cancers occur so deep in the throat they aren’t detected until a late stage.

“Given the lack of reliable screening, prevention is key,” D’Souza says, referring to the HPV vaccine and stressing the importance of outreach and education. To that end, she’s been producing webinars to train providers how to talk to vaccine-hesitant parents, as well as presenting at meetings and writing articles for practitioners of oral medicine

Lately, companies have gotten aggressive with their marketing of saliva HPV tests to dentists, D’Souza reports. “But once dentists tell their patients they have HPV in their mouths, what does that even mean? Essentially, we don’t know. A single, oral HPV DNA test in a healthy person is not likely to be a good predictor of cancer risk,” she says.

In the cervix, it’s only when the infection causes a precancerous lesion or if cancer cells are detected by Pap screening that treatment is warranted.

“HPV-causing cancer really wasn’t understood outside of the cervix until these past few years,” D’Souza says. “Health care providers are just now learning what they need to tell people.”

Although more and more doctors are insisting that adolescent girls and boys should be immunized with the HPV vaccine prior to sexual debut, parents in the U.S. aren’t listening. An April 2013 Pediatrics article reveals that the number of parents who worry about the safety of the HPV vaccine and don’t intend to get their teens vaccinated rose dramatically (from 4.5 percent to 16.4 percent) from 2008 to 2010. In fact, only about 30 percent of teens have been immunized with the HPV vaccine, according to the American Cancer Society

“It’s a tragedy the rates in the U.S. are so low,” D’Souza says, citing countries such as Australia and England where school-based vaccination programs have resulted in compliance rates as high as 90 percent. “It’s going to protect the younger generation [from cancer] if we can improve our uptake of the vaccine.”

The situation is even worse in developing countries. Worldwide, the numbers of women developing cervical cancer and dying from it annually remain unnecessarily high. Cervical cancer death rates are not dropping in places where screening is limited and the cost of preventive vaccines, prohibitive; in Shah’s native India, for instance, as well as in Taiwan.

T.C. Wu set out from Taiwan in 1984 and has been a Shah protégé ever since. “The whole story of me has 100 percent to do with Keerti,” Wu says.

With a new medical degree and new wife, Wu was 27 when he left home on an extended honeymoon trip that involved his bagging a master’s degree in public health from Johns Hopkins. That’s where his life plan of becoming a surgeon bumped up against Shah, and promptly derailed.

“I attended a lecture given by Keerti who was talking about a new virus that was found to be associated with cervical cancer,” Wu recalls. “All the textbooks said it was herpes, but here he was talking about the human papillomavirus. Because of that lecture, I spent the next five years [at Johns Hopkins] studying molecular biology related to a tiny virus.”

Wu, MD, PhD ’89, MPH ’85, is a professor of Pathology, Oncology, Obstetrics and Gynecology, and Molecular Microbiology and Immunology who now directs a long-term Hopkins-based project to develop vaccine strategies for the prevention and treatment of diseases caused by HPV.

During his graduate studies here, Wu became intrigued by the idea of using immunotherapy to target HPV-associated cancers. At the time, Shah had in place an HPV program that allowed Wu to accomplish an ambitious first step toward that goal: He created a mouse model of cervical cancer on which therapeutic vaccines could be developed and tested.

“We called it TC1,” Wu says, adding that the mouse name refers to “Tissue Culture 1” and not himself.

For the past nine years, he has headed up research efforts for a program that relies on extensive teamwork among the Hopkins community and receives the largest translational research funding for cervical cancer vaccine research provided by the National Cancer Institute, amounting to $14.4 million per five-year cycle.

The program, called the Cervical Cancer SPORE, is associated with several ongoing clinical trials of a new generation of relatively inexpensive vaccines that could protect women against more than 90 percent of all cervical cancers.

Everybody, including Shah, thought a therapeutic vaccine would be the quick and easy bow on top of the neatly tied-up HPV success story. Unlike the prophylactic HPV vaccines that produce antibodies to prevent viruses from growing, a therapeutic vaccine would work by looking for antigens in cancer tissue and attacking them. In the case of HPV, a viral antigen is present in every single tumor cell, so success seemed clear-cut, Shah says.

Therapeutic vaccines in development have cured thousands of mice seeded with cancer cells. None has yet cured humans. However, with continued efforts, the therapeutic HPV vaccine may soon become available.

When surveying the whole of HPV research—its past and future—Shah alludes to a paragraph in Lewis Thomas’ Lives of a Cell that describes scientific activity. For a long time, nothing makes sense. There are many false leads as people buzz about; bits of information fly here and there, as if somebody had disturbed a beehive.

And then, Shah recites this passage:

“There suddenly emerges, with the purity of a slow phrase of music, a single new piece of truth about nature.”