December 17, 2001
A critical area of research focus in HIV pathogenesis is to determine the causes of variability in the rate of HIV disease progression. While on average the time from acquisition of HIV infection to AIDS is 10-12 years, there are some people who progress much more rapidly, others more slowly. At the extreme end of the slow progression are the rare individuals who appear not to progress at all -- they are characterized by having HIV RNA levels <50 and normal or near-normal CD4 cell counts even in the absence of HIV treatment. In his presentation entitled "Immune Reconstitution in HIV Infection," Dr. Mark Connors from the U.S. National Institutes of Health (NIH) provided some insight into the characteristics of this rare situation.
Sixteen patients provided blood samples for study. In a case-definition more rigorous than other "long term non-progressor" studies, enrollment required that all participants have HIV RNA below 50 copies/ml (apart from occasional "blips" with intercurrent infections), as well as normal CD4 cell counts and normal CD4:CD8 ratios. Many dated their HIV diagnosis to the mid-1980s, and none had experienced opportunistic infections.
Connors' main findings were as follows: First, a specific genetic profile was strongly associated with HIV control, namely HLA-B57, which was found in fourteen out of sixteen patients. Second, and somewhat surprisingly, there was no correlation between the number of HIV-specific CD8 T-cells and control of replication.
In other words, the proportion of CD8 cells that had specific HIV responses was the same in this group when compared with a group of patients who had progressive disease. Third, and also contrary to prior beliefs, rather than having a broad CD8 response to a wide variety of viral antigens, in fact the HIV controllers had more targeted, or focused, responses. Lastly, the CD4 proliferative response seen in these patients was markedly higher than in patients who have progressive disease. This finding is similar to that shown in Eric Rosenberg's and Bruce Walker's important work in the treatment of acute HIV infection -- where early treatment appears to "preserve" some of these immune responses which otherwise may be lost.
However, where Connors' work differs from Rosenberg's work is in the interpretation of the salutatory effects a good HIV-specific CD4 response alone can have on immune control. In looking at a group of chronically-infected patients who had strong HIV-specific CD4 responses, Connors found that cessation of antiretroviral therapy was not associated with virologic control at all. In fact, most of these patients promptly experienced virologic rebound. Furthermore, the strength of the HIV proliferative response dropped dramatically with virologic rebound -- even though the cells to effect this response remained, they simply lost this function. Their persistence allowed the CD4 proliferative response to return promptly when antiretroviral therapy was resumed.
What are the implications of the work presented in this session? Perhaps most importantly, the careful description of the HIV controllers will help guide the surrogate markers which are likely to be critical in vaccine and immune-based therapy development.
Additionally, the data on cessation of treatment in chronically-infected patients suggests that viremia acts to suppress, not stimulate, some HIV-specific immune responses. This finding acts to deflate one of the stated goals of intermittent therapy, though it does not eliminate the other possible advantages of this strategy which are reduction of cost and toxicity.