Crowded around a long wooden table topped with grapes, roasted nuts, and the occasional cookie, more than two-dozen AIDS researchers contemplated the colorful projection before them. "You start out with a simple question and all of a sudden you end up with five years of work," mused Susan Zolla-Pazner, an AAAS Fellow and professor of pathology at NYU Langone Medical Center. "This was a simple little study, right?"
For the past hour, Zolla-Pazner and her colleagues at the Veteran Affairs Medical Center in Manhattan where she holds a joint appointment and heads the AIDS Research Center, had been readying a lab member's presentation for the upcoming AIDS Vaccine conference in Boston. The PowerPoint talk had been primarily about one molecular region of HIV, called V2, but it had catalyzed an animated discussion about V2's interplay with another region, called V3. Zolla-Pazner's comments may have been made in jest, but they underscored the incredibly complex microbiology of HIV and her long history as an immunologist working towards developing an effective AIDS vaccine.
In 1981, in this same unremarkable conference room on the 18th floor of the VA building, Zolla-Pazner joined other NYU researchers in first identifying the fatal disease afflicting homosexual men in New York City. In the 31 years since, she has applied her knowledge of antibody development to AIDS research, examining in particular the body's immune response to the variable regions of the HIV envelope -- the outer casing of the virus that binds to white blood cell receptors.
While HIV is considered a single virus, there are genetic variations of it all over the world. These are largely determined by the sequence of amino acids in the HIV envelope's five variable regions, including V2 and V3. Zolla-Pazner likens these variable regions to our eyes, noses, and mouths — in a room of 100 people, she says, each face will look different but have the same elemental features. Similarly, HIV's variable regions are, by definition, changing, but Zolla-Pazner has found that they have structural components that stay constant. And, in decades of fastidious work, she has come to believe that these conserved structures are key to HIV immunization, because they play a role in HIV infection and we can develop particularly strong antibodies to them that appear to interfere with that process.
Since publishing her first paper on these regions in 1991, Zolla-Pazner has spent the bulk of her career investigating V3 and the body's immune response to that region. In the past few years, she has turned to V2, believing that antibodies to V2 are even more pivotal than those to V3 in protection from HIV infection. Cumulatively, her work has guided the field towards considering the role of antibodies in HIV infection, and ultimately, showing how to harness that immunological response in a potential vaccine.
Until very recently, Zolla-Pazner often felt like a salmon swimming upstream. Few scientists believed, as she did, that these variable regions were worth targeting with a vaccine. "She really stayed the course, and did not let critics unseat her," said Nancy Haigwood, who researches AIDS in non-human primates at the Oregon National Primate Research Center and has known Zolla-Pazner for more than two decades.
It is only in the last year or so, following laboratory studies of a large HIV vaccine clinical trial sponsored by the U.S. Army and the Thai Ministry of Health, that Zolla-Pazner has seen her work increasingly validated by the field. The results from the trial, called RV144, were promising: those who received the vaccine had a 31.2 percent lower rate of HIV infection than those given a placebo. (Zolla-Pazner was not involved in the original trial, but she later sat on an advisory committee convened to make sense of the trial's results and was one of the scientists permitted to further run tests on the trial specimens back at her lab.) In one follow-up analysis published last spring in the New England Journal of Medicine, Zolla-Pazner and colleagues found that antibodies to variable regions 1 and 2 may be responsible for the significant reduced risk of infection seen with the vaccine.
Before RV144, success in developing an AIDS vaccine had been painfully incremental. "Nobody expected us to hit a grand slam the first time we came up to bat," Zolla-Pazner said. "The first three efficacy vaccine trials that were done we struck out." The last strikeout, in 2007, was particularly devastating: vaccination was not just ineffective, it was tied to an increased risk of HIV infection.
With the results from the RV144 trial, Zolla-Pazner said, researchers are now standing on first base. "Now we've got a direction, and we didn't have that before," she said. She concedes they still have a ways to go to produce a safe and effective vaccine that works in the real world, but that's not stopping her from charging ahead: Zolla-Pazner and her colleagues recently received a $12.7 million 5-year grant from the National Institute of Allergy and Infectious Disease to design a vaccine that zeroes in on V2. "It's a hypothesis worth testing," she said.
How has she sustained the conviction to stay this course? A few months ago, Zolla-Pazner was asked this very question. "The answer is very simple. I'm an immunologist and this is an immunological problem," she said. "And I'm an antibody person and I believe antibodies are the answer."