Six Prominent Women Scientists Making a Difference in the AIDS Fight
By Mary Rushton
It is no surprise that the AIDS pandemic, which began 34 years ago, altered the career paths of female scientists. The pathogen was mysterious, inscrutable, and killing millions of people around the world. Before long dozens of scientists, male and female alike, began studying this new human virus. Their efforts are transforming the fields of virology and immunology.
“The minute I started working in infectious diseases, to me there was no other infection I wanted to work on more than HIV,” says Sharon Lewin, director of the Doherty Institute for Infection and Immunity in Melbourne, Australia, and a prominent HIV cure researcher.
French virologist Françoise Barré-Sinoussi is arguably the most famous female in HIV research. She and her colleague Luc Montagnier of the Institut Pasteur in Paris received the Nobel Prize in Physiology or Medicine for co-discovering HIV, along with US researcher Robert Gallo. Barré-Sinoussi is now one of the most influential scientists directing HIV cure research.
Women are also now steering global AIDS treatment programs. Deborah Birx was appointed Ambassador at Large and US Global AIDS coordinator in 2014, putting her in charge of all US government international HIV/AIDS efforts. This includes overseeing the US President’s Emergency Plan for AIDS Relief (PEPFAR)—considered the biggest humanitarian effort since the Marshall Plan. Her prior posts include serving as director of the Department of Defense’s US Military HIV Research Program (MHRP). While at MHRP Birx oversaw the launch of the RV144 vaccine trial in Thailand, the first and thus far only trial to show vaccine-induced protection against HIV.
Precisely how many women are studying HIV/AIDS and how this compares to other diseases is difficult to say, although men certainly outnumber women no matter what the scientific discipline. A more sobering statistic that resonates with AIDS researchers is the toll the epidemic takes on vulnerable populations, particularly women. According to the Joint United Nations Programme on HIV/AIDS (UNAIDS), 64% of new adolescent infections in 2013 were among young women and more than half of people living with HIV/AIDS are now women. In sub-Saharan Africa, young women aged 15 to 24 are almost twice as likely to become infected with HIV as their male counterparts, according to UNAIDS data. HIV/AIDS is also the leading cause of death among women in their reproductive years (ages 15-49). Advances in HIV prevention, including the use of antiretrovirals to prevent HIV infection, together with development in AIDS vaccine and cure research may reverse these trends.
We talked with six leading women scientists from the US, Australia, and Africa, to learn more about their careers and what inspires them to continue battling HIV/AIDS more than 30 years into the pandemic.
With more than six million people living with HIV/AIDS—around 3.5 million of them women—South Africa is ground zero of the HIV pandemic. South Africa continues to shoulder the biggest burden of HIV/AIDS in the world even though the number of new infections has been declining since 2000 and the number of AIDS deaths has been dropping since 2010. It is in this context that Linda-Gail Bekker works as principal investigator and chief operating officer of the Desmond Tutu HIV Centre. Bekker planned to become a geriatrician, but a clinical rotation in KwaZulu-Natal in the 1980s pushed her toward HIV and tuberculosis (TB) research. In Cape Town she works alongside her husband, Robin Wood, who is director of the Desmond Tutu Centre. She is also the President-Elect of the International AIDS Society (IAS). Bekker will be the first female African to hold this position when she takes office at the 21st International AIDS Conference in Durban in 2016.
Are the prevention and treatment programs for HIV and TB succeeding in South Africa?
Linda-Gail Bekker: South Africa has carried an enormous burden of HIV since the 1990s and now the biggest worldwide. Unfortunately, a period of AIDS denialism slowed down access to antiretroviral treatment [ART], but attitudes have shifted and the new health administration is now grappling with the day-to-day challenges of getting more people into treatment. There is a real sense of urgency, although health systems are groaning under the load. With TB, I’m afraid we haven’t had epidemic control for more than 100 years. Unfortunately, we don’t fully understand what is needed to interrupt transmission so more research is the way to go.
How did you deal with the issue of AIDS denialism in South Africa professionally and personally?
LB: On a certain level it was embarrassing hearing these dreadfully wrong statements. And when asked why these notions existed in government, to this day I don’t really have a good answer. Researchers and clinicians did a fantastic job of working around the barriers and obstructions. Academic researchers haven’t always agreed with activists in the history of the AIDS epidemic, but in this case civil society formed an alliance and took on the government, providing incontrovertible evidence that, amongst other things, maternal-to-child transmission of HIV can be prevented with antiretrovirals. On other occasions we joined the government and took pharmaceutical companies to court to drive down the cost of antiretrovirals (ARVs) and other critical medications. Thankfully, with the start of PEPFAR there were other ways to fund ARVs and now South Africa has the biggest treatment program in the world. This is something to celebrate!
What are some of the innovative ways your centre is tackling HIV?
LB: One of the challenges we face in the region is tracking people who move between clinics and are lost to follow-up, so we are testing a biometric system that captures patient fingerprints electronically, along with their medical history, and stores the information in a confidential website. Names are often interchangeable and hard to track—biometric identifiers such as fingerprints are not. Long ago, we also realized the merits of task shifting. We trained community care workers living with HIV to be adherence counselors in order to ensure that people with HIV remain in care. Many of these participants now are the cornerstones of our treatment programs.
Last time the IAS Conference was held in Durban in 2000, the major theme was expanding access to treatment in developing countries. What are the key issues on the agenda for 2016?
LB: I think we are at a critical crossroads. The prevention revolution is truly underway. We have tools to help end the epidemic but we’re going to have to take bold steps. Now is the time for full investment and a worldwide concerted and courageous effort. I also think with the converging of global health issues, there are critical lessons we have learned from the HIV/AIDS response that can and must be brought to bear to change the way we do business in public health throughout the world, particularly in those areas where there are still significant healthcare disparities.
Ambassador at large and US Representative for Global Health Diplomacy Deborah L. Birx is the fourth Global AIDS Coordinator in charge of the PEPFAR—a US$6. 6 billion program in 65 countries that supports HIV/AIDS treatment and prevention efforts through bilateral and regional programs. This includes supporting life-saving antiretroviral treatment for 7. 7 million people. She also oversaw the launch of the RV144 trial in Thailand as director of MHRP and served as the director of the CDC’s Division of Global HIV/AIDS. Not bad for someone who seemed headed for a career making a better green dye.
How did you become involved in HIV/AIDS?
Deborah Birx: In 1983-84, I was a clinical immunologist doing a joint fellowship at the NIH [US National Institutes of Health] and Walter Reed Army Medical Center. I was working on primary immunodeficiency—stuff like the “boy in the bubble”—when we started getting consulted about patients with this mysterious immunodeficiency. We didn’t know what it was at first so we started analyzing their B cells. I was more compelled by the patients, their generosity and human spirit, than I had been with any other disease that I had worked on and I just never left.
And when did you decide on a career in immunology?
DB: My two elder brothers were mathematicians and nuclear physicists, my father was an electrical engineer and mathematician, and my mother taught nursing. In our household, math and science were extraordinarily valued. So not to be the loser of the family, I went to college and majored in chemistry but soon realized that the best jobs in the mid-1970s were making a better green dye at Kodak so the photographic paper wouldn’t turn yellow. I realized that I didn’t want to spend the next three decades doing that, which is a good thing because when digital cameras came out that skill would have been completely worthless.
A cadre of leading scientists criticized the rationale for the RV144 trial, which you oversaw. Were you skeptical about this trial?
DB: I like to believe I am always a skeptic about data and pushing the envelope to understand things in a deeper way. But that Thai trial was only possible, I think, because at the Department of Defense (DOD) you had the ability to fail spectacularly and yet still have a safety net underneath you. I mean, to have all these premier scientists write about how the DOD under the direction of Debbie Birx was probably doing one of the stupidest things on the planet! If we hadn’t been supported by DOD and the NIH that trial could have been shut down before we got started. There was a casualty, however. We had written a companion protocol to the trial which would have put tissue, serum, and plasma samples from a subgroup of vaccines and placebo recipients away so if the [RV144] trial showed promise we would have the ability to do an in-depth immunological analysis of correlates of protection and correlates of immunity. That companion study was stopped. Roll forward 10 years when we found some evidence of vaccine efficacy and everyone is saying, where are the samples?
What was your experience like at the CDC?
DB: It was clear from the amazing success that the Kingdom of Thailand had in controlling the epidemic that doing a series of vaccine trials there in the general population was going to become more and more difficult. So in 1998 we began setting up extra sites in Uganda, Kenya, and Tanzania. At that time, from 1998-2000, we wanted our investment in research to also support those areas in Africa with additional lab support and potential clinical support. Day after day at the [Kenya] field site I was primarily associated with, wheelbarrow after wheelbarrow of very sick children, Moms, and Dads were wheeled to the gates of the district hospital. The matron of the hospital, who was an extraordinarily dedicated woman, would turn them away saying, you know we don’t have anything to treat them with so there really is no reason to bring an HIV-positive patient who is dying to the hospital because it is just a drain on resources and nothing could be done to save them. This was not callous. They had witnessed thousands of deaths in the community. So here we were talking about doing molecular biology, spending millions of dollars on fundamental research and vaccine development, and you have an entire community dying outside your research walls. It was just too overwhelming and shocking.
And so when PEPFAR was announced by President Bush in the State of the Union address in January 2003, I flew back from Kenya to try and convince Joe O’Neill, the White House AIDS czar responsible for implementing PEPFAR, to include the broader DOD community in PEPFAR, especially the groups doing HIV research that were on the ground and could jumpstart the program with small amounts of funding. I knew if we continued to do research there and only treated a person who became HIV infected during a clinical trial, the very culture of Africa would require that the family split the pills because they believed fundamentally in the wholeness of the community. I’m still grateful to Joe for allowing the US Military HIV Research Program to be part of PEPFAR.
What is one of the biggest challenges in your current role?
DB: I come from bench-driven research where data is honored. It’s been challenging to figure out how to present data so it is understandable and actionable. We created the PEPFAR Dashboards to make our data accessible to all. It allows for transparency and accountability, which are priorities for us. We are taking slow steps forward but I have been witness to the last 30 years of the epidemic, the sheer magnitude of it—30 million people have died—and I guess I never think we do enough or move fast enough.
Sharon Lewin, Director of the Doherty Institute for Infection and Immunity in Melbourne, Australia, credits her post-doc training with David Ho at the Aaron Diamond AIDS Research Center in New York City with solidifying her interest in finding an HIV cure. Ho’s seminal findings that triple-combination therapy could so effectively and dramatically reduce the levels of HIV to the point where they were undetectable marked a turning point in the pandemic. However, initial theories that it might also eliminate the virus over time proved premature, prompting researchers like Lewin to try and figure out why.
What drew you initially to HIV research?
Sharon Lewin: The minute I started working in infectious diseases, to me there was no other infection I wanted to work on more than HIV. There were so many areas that were fascinating to me. The science was changing so quickly and there were all these challenging issues around consent, stigma, and patient inclusion. This was the late 1980s. There was no real treatment—largely, gay men were getting infected in Australia—and lots of people were dying. So there was this real urgency to do something.
When did you start focusing on cure research in particular?
SL: My PhD was actually quite relevant to HIV latency and persistence. In those early days, we were still trying to work out which cells HIV really infected. We always knew it infected T cells but there was this question about what other longer-lived cells there were. Then in 1997, I got an opportunity to do my post-doc with David Ho. At the time he and a colleague, Marty Markowitz, had some of the best-studied patients being treated with antiretroviral therapy. Some of the early modeling predicted that if you stayed on treatment for three years, the virus would decay to nothing. But that theory only lasted about three or four months when scientists discovered HIV latency—that pools of latently infected cells known as the reservoir were present from the beginning and persisted indefinitely on antiretroviral therapy. The first paper appeared in November 1997, two weeks before I arrived in New York, and so I became involved in that whole pursuit of can ARVs cure HIV and if they can’t why and where is the virus sitting in people on ARVs.
What was it like working with David Ho in the 1990s?
SL: The whole environment at Aaron Diamond at the time was just really amazing. David was incredibly innovative—he had a million different ideas—and there were people there from all over the world getting training.
What is the focus of your cure research?
SL: I’ve worked in three main areas. The first was how to mimic HIV latency in in vitro models. I had been involved in developing tools that allowed us to ask the question of how latency is established and how can we intercede. We were the first to describe that you don’t have to fully activate the cell but just stimulate certain pathways to allow the virus to get in and integrate. That meant we could then look at drugs that reverse latency or activate latency, where you basically push the virus out of its hiding place in the hope it then will kill the cell or become visible to an immune response. This is what is now called the “shock and kill” or “kick and kill” approach.
We were one of the first groups to look at these more potent histone deacytylase [HDAC] inhibitors like valproic acid. At the same time, in the mid-2000s, HDACs like vorinostat were exploding in the cancer world and they were 1,000 times more potent. And of course now we have HDACs that are 1,000 times more potent than vorinostat.
Why did it take the HIV cure field another decade to really take off?
SL: I think there were many other priorities in the 1990s regarding HIV care, such as toxicity and drug resistance, to sort out. There was a lot of interest in developing a vaccine, which remains of critical importance. I think those two issues really dominated research. I think the cure field as a whole really took off about five years ago with the Berlin patient [the only person to be cured of HIV] and leadership from people like Francoise Barré-Sinoussi and the IAS. Until then there was a lot of skepticism about whether we could cure HIV. By 2010, it had also become apparent that we had really good drugs, costs were lower, and we could get them into Africa. The question was how sustainable was this?
Do you think a cure is possible?
SL: There are a lot of challenges but I do think the field has moved a lot in the last five years. There are reports of people who have been able to safely stop treatment and achieve antiretroviral-free remission for a period of time. Plus, if you treat people early you can significantly reduce the amount of latency. There are also drugs that clearly activate the virus and push it out of its hiding place. I think we will find more defined ways to achieve antiretroviral-free remission, though how many people will be able to achieve that and for how long I’m not sure.
What advice would you give to women considering a career in science?
SL: I think women should follow their passion whatever it is. In the end you are judged by how good you are and that is often directly related to how passionate you are. I look at someone like Françoise [Barré-Sinoussi], who was trained and doing her major work in the early 1980s. It was a different time then and much has changed. But there are still immense challenges with families, kids, and finding success in research. I don’t think that can be overlooked. I don’t think it is the same for men. At the time when your scientific career is probably at its busiest, it is also when you are having kids. We need better systems in place to account for that.
You could say that Galit Alter, an immunologist and principal investigator at the Boston-based Ragon Institute of Massachusetts General Hospital, the Massachusetts Institute of Technology, and Harvard, plays the field. It’s the goal that remains the same: finding an AIDS vaccine. Alter’s earliest research focused on the role of T cells. At the time, hopes were riding on a T-cell based vaccine candidate being tested in an efficacy trial known as the STEP study. But when the STEP candidate was found to be ineffective, Alter switched her career focus. She is now studying sugar molecules that enhance the production of antibodies.
How did you came to study HIV and antibodies?
Galit Alter: I was working toward my PhD when people started recruiting HIV-positive people for acute infection studies. That was when there was a lot of momentum and excitement around T-cell biology. But then STEP failed and I didn’t want to be in T cells anymore. My inclination has always been to do something a little bit different. If everyone is playing in the sandbox, I want to find a different sandbox. I was working in T cells before it got really popular. Then when everyone jumped on the bandwagon I switched to natural killer [NK] cells. Then when the NK cell field got too crowded, I jumped to antibodies. And now that antibodies have gotten popular, I have jumped to sugars. You have to keep pushing barriers. If you don’t push yourself to explore new frontiers you end up not being funded because you keep doing the same old, same old.
What are you learning about sugars or glycans and their role in vaccination?
GA: What we know is that these glycans change during inflammatory diseases. People with autoimmune diseases have different glycan profiles than people who don’t have autoimmune diseases. Pregnant women and older people have different glycans and we know they change during different inflammatory states. Whether they are selected in different ways in vaccination is not totally clear. But these glycans are, selectively, probably being programmed by B cells under different kinds of inflammatory cues, and understanding how they are regulated is really a black box and sort of where my efforts are. What we’re seeing is that different antigen-specific antibody populations all have their own antibody glycan signature that allows them to direct different kinds of functions. That suggests that B cells can learn this. The question is how do they learn this and how can you develop a vaccine that induces that in a selective way.
What tools are you using to answer these questions?
GA: Well, glycans are not easy to study. They are kind of the overlooked molecule because the tools haven’t been right, but better tools have been emerging over the last decade due to a massive investment from the NIH, which has basically been creating these centers to help develop newer approaches to analyzing glycosylation. With help from some of the gurus in glycomics we’ve been able to adapt high throughput techniques to study hundreds of thousands of antibody populations. It’s being done all in house, which gives us the opportunity to tackle all kinds of cool questions.
Did you always know you wanted to be a scientist?
GA: I had no idea and I think it was serendipity that I ended up in HIV research. I stumbled on microbiology and immunology and found viruses really interesting.
As the AIDS epidemic decimated sub-Saharan Africa, Kenyan Nelly Mugo was beginning her clinical career in obstetrics and gynecology. Nearly two decades later, the principal research scientist at the Kenya Medical Research Institute is part of an AIDS success story. Mugo helped conduct the Partners PrEP Study and the Partners Demonstration Projects that showed pre-exposure prophylaxis (PrEP)—the administration of ARVs to prevent HIV transmission—was effective in serodiscordant couples.
What convinced you to become a researcher?
Nelly Mugo: I was working at a hospital in Kenya and we were seeing a lot of complications from pelvic inflammatory disease, especially in HIV-positive women. I thought better research might help improve the clinical care and so I began working with Craig Cohen [a US researcher now at the University of California in San Francisco], who had helped establish the Research Care and Treatment Program in Nairobi. I later got my Masters of Public Health at the University of Washington specializing in epidemiology.
What was it like being on the front lines of the epidemic before there was effective treatment?
NM: It was a tragedy and a very fearful time. There was so much ignorance even among health care providers. There were some who were afraid to treat people and people died from the stigma associated with AIDS. It was a terrible time for our healthcare system.
What is the status of PrEP in Kenya now?
NM: The Partners Demonstration Project found that daily PrEP use among serodiscordant couples was even more effective than we thought. I’m very excited about that. There is still a lot of advocacy that we need to do around PrEP—who should receive it, how will they access it, and the role of providers in implementing PrEP. That’s what we need to understand. Working with our colleagues from the University of Washington we are committed to working with the government to see PrEP move from research to practice.
A decade into her career as a B-cell immunologist, Susan Zolla-Pazner was consulted about a handful of cases of Kaposi’s sarcoma occurring among homosexual men in New York City. This thrust her into the forefront of an epidemic that has come to define her life’s work. Zolla-Pazner has spent most of her career studying antibodies against HIV and using this information to design vaccine strategies, concentrating in particular on certain variable regions of the outermost viral protein known as HIV Envelope. Much of her work involves the second and third variable loops of HIV Envelope, referred to as V2 and V3 respectively. Zolla-Pazner was not involved with the conduct of the RV144 trial in Thailand, however, her subsequent work demonstrated that the modest protection against infection among vaccinated volunteers correlated with vaccine-induced antibodies targeting V2. After 45 years at New York University, Zolla-Pazner is moving across town this summer to join the Icahn School of Medicine at Mount Sinai as a professor of medicine in the Division of Infectious Diseases and the Department of Microbiology.
How did you get involved in HIV research?
Susan Zolla-Pazner: I finished a post-doc and started a faculty position at New York University in 1969 working on multiple myeloma and focusing on B-cell immunology. In 1981 I got a call from a physician who had had four male patients with an unusual cancer called Kaposi’s sarcoma [KS], which I had never heard of before. Those were the first four patients with KS associated with what we later found out was HIV infection.
That must have been quite an interesting time.
SZP: It was like living in the middle of an Agatha Christie novel. There were only a handful of people who had an inkling of what was going on. When we realized that what we were seeing was occurring in gay men, we contacted a physician in New York who treated mainly gay men and we asked for blood specimens from 40 healthy gay men so we could match them to the first 20 patients we had with KS. We found that a third had the same immunologic abnormalities as the KS patients. I remember sitting down and pouring over the data and realizing that a third of the gay population was already suffering from this strange malady. It still gives me the shivers.
Can you describe the early days of your work on AIDS?
SZP: I was interested in antibodies and I was particularly focused on B-cell abnormalities in patients, which was pretty peculiar at the time because everybody was focused on T-cell responses. What we noticed right away was that all patients had elevated levels of Immunoglobulin G (IgG), and that their B cells were quite activated. By the late 1980s, early 1990s, Genentech (VaxGen) and Chiron developed their gp120 vaccine candidates. When it appeared that the vaccine-induced antibodies were not providing any virus neutralizing activity, the field turned to T cells. And for 15 or 20 years it was pretty lonely working on antibodies. You would go to meetings and antibodies would always be discussed on the morning of the last day.
Were you surprised by the results of the RV144 trial?
SZP: I was astonished. All of the work I had done up until then had suggested that the V2 and V3 regions of HIV Envelope were involved. It was hypothesis-driven and hypothesis-based on a good 20 years of research. What I was most astonished by was that V2 antibodies were the only correlate of reduced risk in RV144; that I never, never would have expected. I still don’t think it is the only correlate. I think we just have to know what to look for and we’ll find new correlates, but in RV144 it was the only one significantly associated with reduced risk and our findings were subsequently supported by many different streams of data produced by many different labs independently, so I don’t think there is any question that it is real, even though there are still some naysayers.
There is so much excitement centered on antibody-based strategies lately. How much of that is due to better tools and technology?
SZP: The generation of monoclonal antibodies, the ease with which antibodies can be crystallized so you can view the epitopes, and the explosion in bioinformatics have been important, but again I think that the RV144 trial was the turning point. The previous large-scale efficacy trial was the STEP Trial. Being in the HIV field when the results of that trial were announced was like being at a wake. It was devastating. So the marginal protection observed in RV144 was something the field really needed.
What is the status of your vaccine research efforts?
SZP: I am always sort of an outlier. When the field was focused on T cells, I was interested in B cells. There is now a tremendous amount of interest in [Envelope] trimers as immunogens. The B-cell lineage approach is another hypothesis that deserves to be looked at very carefully. Both approaches are very different from one another but they are both aimed at inducing these incredibly potent neutralizing antibodies, which I refer to as “Michael Jordan antibodies.” They are very broad and very potent, but only a small proportion of HIV-infected individuals make them and they require extensive somatic hypermutation, so the probability of inducing those antibodies through vaccination is small. I hope I’m wrong, but that is how I feel. What RV144 showed us is that you don’t need these exceptional antibodies for protection. There was no indication from that trial that anyone made them. The vaccine induced conventional antibodies to V2 and V3, as well as to other Envelope regions, which essentially every infected person makes. So our view, which is an outlier’s view, is that if we can focus the immune response on the V2 and V3 regions of the molecule, we will induce antibodies that will not be as potent or as broad as the broadly neutralizing antibodies, but may be effective. Our approach is to design epitope-scaffold immunogens that direct antibodies to the V2 and V3 regions. Most of our work has been done in rabbits but we are in the midst of moving into monkeys. We are looking at both active and passive immunization approaches.
How many years away is an AIDS vaccine?
SZP: I’m hoping we get lucky but I don’t know how long it’s going to take. From a purely immunological point of view, the work we do is fascinating. From a humanitarian view, this epidemic is devastating. The combination of those things keeps driving us.
Mary Rushton is a freelance writer based in Cambridge, Massachusetts.