The factors that determine the rate of HIV disease progression are ill defined, yet essential to understand in order to develop vaccine and therapeutic strategies. Prior to HAART, the average rate of progression to AIDS in the United States was ten years. However, a minority of individuals, despite remaining untreated, maintain normal numbers of CD4+ T-cells, low to undetectable copies of viral RNA and do not present with clinical manifestations of disease for ten, or even twenty years. Little is known about what makes these long-term nonprogressors (LTNP) unique in their ability to control viral replication and slow disease progression. We, and others, have found that HLA-B*57+ individuals are over-represented in LTNP. In some studies 85% of LTNP are HLA-B*57+ suggesting they express some unique genetic feature that contributes to slower disease progression. Because HLA class I antigens present epitopes to CTL, we hypothesize that HLA-B*57 contributes to slower disease progression by influencing the CTL response to HIV. Indeed, we, and other, have found that HLA-B*57+ LTNP mount CTL responses to 3 or more conserved viral epitopes, which would diminish the ability of the virus to mutate away from epitope-specific CTL. However, expression of HLA-B*57 is not sufficient to confer LTNP status as many HLA-B*57+ people progress to AIDS within 10 years if left untreated (Progressors). These Progressors also mount CTL responses to these conserved epitopes, suggesting that targeting of these epitopes is not sufficient to slow disease progression. However, a major caveat to this data is that these studies have been all performed years after the establishment of HIV infection, and firm conclusions regarding early immunological events cannot be made. There is a need for studies to investigate HLA-B*57+ individuals soon after HIV infection. We hypothesize that LTNP mount CTL responses to more conserved epitopes earlier in HIV infection than Progressors. However, as the rate of disease progression is likely to be multifactorial, we further hypothesize that HLA-B*57 men are over-represented in cohorts of LTNP because, prior to infection, these individuals encounter antigen, either HIV or other pathogens, that prime T-cells capable of responding to HIV quickly and with higher affinity T-cells than found in a primary immune response. Together with the ability to target conserved epitopes, this faster response allows the host to gain immunological control. We have unique specimens from HLA-B*57+ individuals taken both prior to, and early after, HIV infection to that we will use to test our hypothesis. ? ?
| Brennan, Catherine A; Ibarrondo, F Javier; Sugar, Catherine A et al. (2012) Early HLA-B*57-restricted CD8+ T lymphocyte responses predict HIV-1 disease progression. J Virol 86:10505-16 |
