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 Gerald Pierone, M.D., an HIV clinician/researcher and the founder and executive director of the AIDS Research and Treatment Center of the Treasure Coast in Fort Pierce, Fla.
Peter Hunt, M.D.
Can you walk us through your abstract? What research did you do, and what did you find?
Many people have focused on this rare group of HIV-infected patients called "elite controllers," who can control viral replication in the absence of therapy. Particularly, vaccinologists have been focused on these HIV-specific immune responses to figure out correlates of natural protection.
We've examined them from a different point of view. We've wondered whether these strong HIV-specific immune responses they developed might actually have negative consequences.
We and others have shown that patients with high levels of T-cell activation tend to progress more rapidly to AIDS and, in the setting of treatment, gain fewer T cells during suppressive antiretroviral therapy. We wondered whether these elite controllers, while exhibiting strong HIV-specific immune responses, might have abnormally high levels of T-cell activation too, which might be a bad thing.
In fact, we found that they do. Compared to uninfected patients, they have much higher levels of activated CD8+ T cells. They even have higher CD8+ T-cell activation levels than treated patients maintaining viral suppression.
If you look at their CD4+ counts as a group, many [researchers] studying elite controllers will also select patients based on their CD4+ count. There will be elite controllers controlling the virus, but [there will] also be long-term non-progressors maintaining normal CD4+ counts.
We're only selecting patients based on their virologic control, and we include some patients who have actually progressed. In fact, as a group, they have lower T-cell counts than HIV-uninfected patients. In the 7% of our sample that had progressed to AIDS, one had developed KS [Kaposi's sarcoma] at a reasonably normal CD4+ count, and three others were maintaining very low, declining T-cell counts below 200. In fact, the more T-cell activation these folks had, the lower their CD4+ count.
What measures of immune activation did you look at in the study?
We looked at coexpression of CD38 and HLA-DR on both CD4+ and CD8+ T cells. Most of the abnormal increases in activation that we see are driven by HLA-DR expression. There have been some high-profile publications recently linking a high HLA-DR expression in elite controllers to the control of the virus.2
CD8+ cells express these high levels of HLA-DR [that are] more capable of controlling viral replication, but what we're showing here is that there may also be a negative consequence to that. Those with the highest levels of DR expression actually have the lowest CD4+ counts; many of them had progressed.
In this panel [in Dr. Hunt et al's poster, see the two graphs underneath the title "Elite Controllers with Higher HIV-specific T cell Responses Have Higher T cell Activation Levels"], we're showing that those with the strongest HIV-specific T-cell responses -- again, that's a direct measure of the response we think is controlling viral replication -- those with the highest responses also had the highest levels of T-cell activation.
We think there's a balance going on here that, while the strong HIV-specific T-cell responses are contributing to control of the virus, they're also resulting in generalized inflammatory consequences which might lead to CD4+ depletion.
Your research has shown that linkage by the fact that these patients with greater levels of immune activation tended to have lower CD4+ cells.
Do you have longitudinal data as well, or was this more of a snapshot?
This is a cross-sectional study, a snapshot. We can't prove cause or consequence here, but there is a lot of evidence outside of the elite controller literature to suggest that T-cell activation predicts subsequent CD4+ decline.3-6
There are some other posters at this meeting that show that phenomenon as well.7 I think that's new information for many clinicians. The sense, I think, is that if someone is an elite controller, then they have no worries. But in fact, if these individuals tend to have greater levels of immune activation -- as your study and perhaps others are showing -- then they may have a downward trend to their CD4+ count and can even develop AIDS.
That's right, that's right.
OK. Very good. Thank you.
This transcript has been lightly edited for clarity.
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