February 6, 2008
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There's nothing like hearing the results of studies directly from those who actually conducted the research. It is these women and men who are transforming HIV treatment and care. In this interview, you'll meet one of these impressive HIV researchers and read an explanation of the study he is presenting at CROI 2008. The interview was conducted by Dr. Gerald Pierone, an HIV clinician/researcher and the founder and executive director of the AIDS Research and Treatment Center of the Treasure Coast in Fort Pierce, Florida.
This is Gerry Pierone from the AIDS Research and Treatment Center of the Treasure Coast, here with Richard Novak.
Richard Novak, M.D.
Hi, my name is Rick Novak. I'm from the University of Illinois in Chicago.
Tell us about your poster.
The title of my poster is, "Prevalence and Characterization of HIV-Specific Adaptive Immune Responses in Genital Mucosal Secretions from a Cohort of High Heterosexual Risk, Seronegative Women in Chicago."1
What did your study do and what does it show?
We followed a cohort of high-risk, HIV-negative women that was part of HIV preventive vaccine research. We had also recruited a comparatively low-risk cohort; we defined risk by their risk behaviors. By and large, our high-risk cohort are sex workers, they're commercial sex workers. We collected genital samples from these women and we looked specifically for anti-HIV activity by three different assays: First, we used an assay to measure binding antibodies -- both IgG and IgA -- to gp120 in the genital tract secretions. We also looked at neutralizing activity using three viruses that are taken from a standard panel of viruses that are studied looking for neutralizing antibodies in vaccine trials. That's a cell-based assay. Then we also looked at how antibodies mediate antibody-dependent cellular cytotoxicity.
What we found was that -- after excluding samples that are contaminated by semen, which could be a confounder -- we found that 17% of the women had IgG to gp120 in their genital tracts. Another 4% had IgA to gp120 in their genital tracts. Then there were variable responses to the three viral isolates, ranging anywhere from 11% up to 49% of women who had neutralizing activity to these viruses.
Just to clarify, these are all high-risk women that you're referring to?
Right. They're all high-risk, seronegative women. None of them have HIV. They're all at risk, mostly through commercial sex.
For comparison, in the low-risk women that you've looked at, what percentages might you see, or was that presented here?
Yes, it is. None of the low-risk women had the IgG or IgA antibodies, and none of the low-risk women had neutralizing activity with two of the three viruses. There was one virus to which there was a low level of neutralizing activity; because we see that, it leads me to believe that the activity is probably not antibody driven, but maybe mediated by some other innate anti-HIV factor, of which there are several in the genital tract.
This is fascinating. Can you try to explain what you think is going on here?
We've been interested in this area for some time. The basic premise is that women that we look at who are at high risk for HIV but remain seronegative are in that category for some reason. They're different than women who go on to seroconvert, for some reason. One possible difference might be that they are able to develop an immune response to HIV after exposure. In fact, we're measuring that, and we're finding that some subset of these women do have the ability to neutralize HIV, or they have antibodies specifically for HIV. I don't have the power from this study to say that those are the factors that are protecting them or that they are, in fact, protected by these factors. But the fact that they had these [immune responses] is one way that shows they're different from the low-risk cohort.
Can you postulate any biological explanation for how this might occur?
Through their high-risk behavior, they are getting exposed to HIV, and the mucosal immune response is different. It's just compartmentalized; it's different from the systemic immune response. They're able to mount a local immune response to HIV. It's conceivable that this immune response may be having an effect, protecting them. I can't prove that's true, but there is this correlation.
How do you plan to track this down more definitively?
We want to do other experiments to demonstrate that, in fact, the neutralizing activity is antibody driven. [These experiments will] absorb out the antibodies and show that when you remove the antibodies from the samples, you eliminate the neutralizing activity. We'll try to characterize those antibodies further, through Western blots, to determine which proteins the viruses are binding to. If I have enough material, ultimately I'd like to do epitope mapping on the antibodies to determine if there's a specific segment, presumably of the envelope gp120 or gp41, that the antibodies bind to.
Is your group or any other group doing mucosal studies with biopsies, trying to characterize women's mucosal immune responses in situations like this?
There are a few other people who have done this work over the years and have found some unique antibody responses reaching to gp41 in the genital tract of high-risk women. The biggest group is the one that follows the Nairobi, [Kenya] cohort of sex workers; they've been following a large number of women over many years.2 They're doing similar work and they've found somewhat similar results. They find both humoral and cell-mediated immune responses in high-risk, seronegative women.
Very interesting work. It doesn't get a lot of publicity. Not many clinicians know about this, but it really opens up a whole other avenue for control or prevention of HIV. It seems like it would also be a natural fit for your group to be doing microbicide research, when those agents make it through the pipeline a bit further. Is that something you plan on, as well?
We're part of the HIV vaccine trials work. We do vaccine trials in high-risk women. We're interested in doing microbicides. Right now we're not part of that microbicide network.
Have you seen the news from this meeting that all the vaccines are doomed to failure?3 Are you going to reconsider your vaccine work and try to switch over to microbicides?
No. I realize we [have come up against] barriers with vaccine development, but it's not something we can give up on. I need to make a pitch that, over the years, a number of prevention strategies for HIV [have been developed], and if we were able to implement those fully we would be very successful in stopping HIV transmission. However, a classic example of that is: We've known since the early 1990s that we can prevent mother-to-child transmission with antiviral drugs. However, here in 2008, only 11% of pregnancies are offered medicines to prevent mother-child transmission. That's pretty poor penetration. Last year, it was 10%. This year, it's 11%. At that rate, my great-grandchildren will be taking Spring Break on Mars by the time we can fully implement another transmission prevention. We need other strategies, and we can't give up on vaccine research.
It also sounds like, from your intriguing work, that mucosal vaccines might be a fruitful area for further research.
I absolutely believe so. I also believe that this could lead to a potential correlative community, but I have to say that's a very controversial area. People have worked on this, and many people just don't believe it. I happen to be a believer, and I think if we keep looking at populations of both men and women who are exposed but uninfected, we are going to gain some useful clues as to what immune responses we need to work on to make a vaccine work.
OK, thank you very much.
This transcript has been lightly edited for clarity.
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