By Dana Goldman
As the world grappled with news of an unprecedented outbreak of Ebola virus disease during the past year, more than two million people around the world were grappling with a new HIV diagnosis.
And while AIDS is now managed with medications, something like chronic conditions such as diabetes, that’s not good enough, says Guido Silvestri, chief of the Division of Microbiology and Immunology at Yerkes National Primate Research Center and a professor at Emory School of Medicine.
Paul Johnson, the new director of Yerkes, agrees; that’s why he is ramping up efforts to help write the last chapter on HIV. To do so, he is making connections between Timothy Brown, the first and only patient out of an estimated 78 million affected by HIV to be cured of the disease since it was first identified, and research with nonhuman primates to try to answer the question that is captivating AIDS researchers around the globe: What exactly was it about Timothy Brown’s treatment that cured him?
Brown’s story—detailed in the New England Journal of Medicine almost thirty years into the epidemic—has reinvigorated the field of AIDS research, providing hope that the disease might, in fact, have an end in sight.
“AIDS research made tremendous progress because we were able to identify enough aspects of the virus’s life cycle that can be targeted with certain drugs, but it’s still not ideal,” Silvestri says. “If you’re a person living with HIV today, you need to take the drugs for life. And even if everything goes well and you don’t have a lot of side effects, HIV is still very expensive for society, and there’s still some residual mortality and morbidity. You’re never back to normal. You need a vaccine, and you need a cure.”
Under Johnson’s leadership, scientists at Yerkes and across Emory are working on both. Johnson, who took over as Yerkes director last summer, is furthering research collaborations among Yerkes, the Emory Center for AIDS Research, the Emory Vaccine Center, and Emory’s adult and pediatric infectious disease programs.
Johnson, Silvestri, and their colleagues have several ideas they’re currently testing through research. As part of his treatment, Brown had two bone marrow transplants and received infusions of bone marrow. “A key question for the field is what elements of those procedures were essential for the long-term cure,” says Johnson. Because of medical ethics around experimentation, it’s impossible to replicate that procedure on humans.
That’s why the nonhuman primates at Yerkes are essential. Silvestri has spent his career examining the similarities and differences between simian immunodeficiency virus (SIV) and HIV. Unlike HIV’s effect on humans, SIV does not cause disease in sooty mangabeys, the African monkeys that naturally become infected with it, making it of particular interest to researchers.
It’s been difficult for scientists to figure out how to treat SIV-infected primates in a way that would help researchers pursue a cure for HIV. But, says Johnson, “there are now regimens and combinations of drugs that allow this to be done routinely. The availability of these improved regimens has greatly accelerated interest in HIV cure research in nonhuman primate models.”
Since the news of Brown’s cure, Silvestri has been hard at work using primate models to explore what aspects of Brown’s bone marrow transplants may have made the difference. Says Johnson, “It’s difficult to design these experiments for humans, and Guido Silvestri has established a program here that allows one to look at the components of the bone marrow transplant in nonhuman primates and tease out those necessary for long-term viral eradication.” Those components also may provide information to help researchers develop a vaccine to prevent new cases of HIV.
Silvestri’s lab is working to understand what prevents SIV from becoming a full-blown infection in nonhuman primates, searching for findings that may be applicable to humans. This research, Silvestri says, wouldn’t be possible without the resources at Yerkes. “Yerkes puts us in a position to test hypotheses and concepts in a way we wouldn’t be able to do elsewhere,” says Silvestri.
Meanwhile, Johnson is spearheading a second phase of a research study funded through the Bill & Melinda Gates Foundation, focused on understanding and identifying hidden reservoirs of latent cells carrying HIV. “These cells can be essentially invisible to the immune system and extremely challenging to detect by standard approaches,” he says. To improve detection, Johnson and his team have developed a technique to analyze genes in specific cells so they will have a better chance of eliminating latent cells later on.
Yerkes, says Johnson, “is a robust environment for AIDS research in humans and nonhuman primates. We have a collaborative critical mass of investigators at Yerkes and Emory who are interested in cure research. So the ability to have these investigators collaborate makes this a unique environment.”
Despite the Yerkes advantage, the work of finding a cure and vaccine for HIV isn’t always easy. Conducting new research without new technology is difficult, if not impossible, and technology is expensive. It can be challenging to attract research funding for HIV without pilot studies, and to do pilot studies without funding. “Obtaining that preliminary funding is often one of the biggest barriers that scientists face in their research,” says Johnson.
In addition, he says, finding funding for young investigators is especially challenging given that the success rate for securing National Institutes of Health grants reached an all-time low in 2013.
Driving Yerkes’s success in this environment will be private gifts from people who believe in the research center’s work. “My hope is that the work done at Yerkes will pave the way to identify new concepts and new therapies that can ultimately be translated into clinical practice to help achieve HIV cure,” Johnson says.
Silvestri agrees. “I hope we’re going to develop a vaccine that prevents AIDS and figure out a way to cure the disease for those who are living with it. It’s not going to be easy. It’s not going to happen tomorrow. But we’re so fortunate to have a fantastic group of colleagues, with primates right here, research capabilities, new leadership, institutional commitments, and national and international visibility. I’m very optimistic.”
Meet the Director: Paul Johnson
While Paul Johnson was a student at Harvard Medical School, a mysterious illness began to emerge, first among populations of gay men, on both coasts of the United States.
By the time he graduated in 1984 and began his internal medicine residency at Yale-New Haven Hospital, the AIDS crisis had exploded onto the world health care scene, generating community health care activism across the country and sparking a frenzy of research to identify the cause of the deadly disease, determine how to contain its spread, and find potential treatments.
As a young physician on the front lines fighting a new disease, Johnson was deeply affected by the experience, and has gone on to become an internationally recognized research leader in identification of immune responses that can protect against HIV infection.
In August, Johnson took over as director of the Yerkes National Primate Research Center at Emory. Previously he was director of the New England Primate Research Center (NEPRC) and chair of the NEPRC Division of Immunology and professor of medicine at Harvard Medical School and Massachusetts General Hospital. He succeeds Stuart Zola, who had served as Yerkes director since 2001.
In a conversation with Emory Magazine in October, Johnson explained why he came to Yerkes and what he hopes to accomplish.
Why bring your scientific research to Emory?
Yerkes has a very rich tradition that goes back to the 1930s. It is very well integrated within Emory University and particularly the Woodruff Health Sciences Center. So as a physician, one of the very attractive features here is the opportunity to work more closely within the medical community and to try as director to build those bridges of translational research projects that address human health issues using nonhuman primate research.
What do you see as the ongoing challenges of HIV research?
Continuing challenges are efforts to decrease transmission and improve our prevention efforts. A key component of those prevention efforts would be the development of an HIV vaccine, but it has to be complemented by other measures as well. Despite public education campaigns, new HIV infections continue to occur in the US at a rate of forty to fifty thousand annually, and worldwide that figure exceeds four to five thousand new infections per day.
My particular area of study has been looking at a live attenuated vaccine, in which animals are vaccinated with a weakened version of SIV. The majority of successful viral vaccines in clinical use are live attenuated vaccines because they have the ability to mimic natural infection without inducing disease. For HIV, that balance between efficacy and safety is just too delicate, and so live attenuated HIV vaccines are off the table.
Is that because of the lack of natural ability of the immune system to fight it?
And because HIV infection is forever. A weakening of HIV still poses the risk of sometime in the future that HIV could mutate, avoid host immune responses, and induce disease. So this is not a viable vaccine concept, but it is a way, in an animal model, for us to say what immune responses are important for protection. I think one general theme of what we have learned is that this ongoing, low-level stimulation of the immune system by the attenuated virus is important in order to induce the sort of antibody and T-cell responses necessary to contain or prevent HIV or SIV infection. So the challenge is to try to take this information and develop novel vaccine vectors or vaccine modalities that are able to have some of these characteristics while still maintaining an appropriate safety profile that could be used in human vaccine trials.
How does this influence what is going on at Yerkes?
HIV vaccine efforts are one key area. The other is HIV cure and eradication research. HIV as a retrovirus integrates itself into the DNA of a cell. As long as that cell survives or divides to produce other cells, those other cells will be infected. Although the drugs we have are very effective in suppressing HIV replication, in the vast majority of people who are taken off these antiretroviral drugs, the virus comes back, generally within a matter of weeks. There is a very intensive effort by multiple research groups, and strongly supported by the NIH, to explore ways we can eradicate HIV infection and not require that patients take these antiretroviral drugs for the rest of their lives. There is a very important role that nonhuman primate work will play in terms of identifying the types of cells that serve as the latent reservoir for the infection and determining novel strategies for eradicating those reservoirs. We see this as a very important area for nonhuman primate HIV research for years to come.
What are other areas of strength at Yerkes that you would like to see developed?
One of the things that attracts me is the very vigorous neuroscience programs that are ongoing here. There is ongoing research into behavior, social interactions, and neurodegenerative diseases like Parkinson’s, Alzheimer’s, and Huntington’s disease, as well as psychiatric disorders and autism. I have been working very hard over the past several months to learn more about those research programs and to learn how we can support them moving forward and to increase our ties with people performing neuroscience and psychiatric research within the Woodruff Health Sciences Center. One other area that I want to highlight is the impact of the advances in genetics and genomics that are transforming human clinical care and clinical research. Getting the detailed genetic information from sequencing DNA and RNA from tumors is leading to a better understanding of the mechanisms of carcinogenesis, as well as the development of new therapies. It is affecting the way we give drugs and helping the emerging field of pharmacogenomics, and helping to provide insights into previously undiagnosed diseases, particularly in pediatrics. Those same advances in genetics and genomics that have transformed clinical care are well poised to transform the way we do nonhuman primate research over the next five to ten years.
Are there other aspects of your vision for Yerkes that you’d like to share?
We need to continue to emphasize the training of young investigators. That’s critical for the future of science.