Viral and Cellular Determinants of Pathogenesis
Friday, 10 am - 12:30 pm
Presentation Time: 11:45 am
Background: HIV originated from the simian immunodeficiency virus (SIV) of chimpanzees, which is closely related to the SIV of sooty mangabays (SM) and African green monkeys (AGM). Both SM and AGM have co-existed with SIV for millennia, yet these animals do not develop disease, and are considered “non-progressing” hosts. We have demonstrated that the intestinal tract is the major target for infection and CD4+ T cell depletion in SIV-infected macaques, due to the abundance of activated CD4+CCR5+ T cells residing here. These viral “fuel cells” are the major site of viral replication and CD4+ T cell depletion in SIV-infected macaques at all stages of infection, a finding that has been recently confirmed in HIV-infected humans. In this study, we compared percentages of these intestinal “fuel cells” in progressing (rhesus) and non-progressing (SM and AGM) hosts.
Methods: Lymphocytes were isolated from the intestinal tract, lymph nodes, and blood of 3 uninfected sooty mangabeys, 12 African green monkeys, and 5 rhesus macaques, and percentages of CD3+CD4+ T cells and effector memory CD4+ T cells (CCR5+CD45RAneg) were compared by 4-color flow cytometry.
Results: In normal macaques, ~50% of the T cells in the intestine were CD4+, and ~50% of these co-expressed CCR5. However, fewer than 10% of the T cells in the intestine of AGM expressed CD4, and of these, only ~12% co-expressed CCR5. Sooty mangabeys had larger percentages of intestinal CD4+ T cells than AGM, but essentially none (<3%) of these co-expressed CCR5. All differences were highly significant (p < 0.01).
Conclusions: In normal humans, macaques, and all other species tested, effector memory CD4+ T cells comprise a major proportion of the intestinal T-cell pool. In progressing hosts, these cells are selectively depleted in SIV and HIV infection, and turnover of these cells serves as “fuel” for active viral replication. Remarkably, we found that these cells are essentially absent in both uninfected sooty mangabeys and African green monkeys. The striking absence of activated, memory CD4+CCR5+ T cells in their tissues suggests that co-evolution of these natural hosts with SIV over millennia has resulted in the selection of animals that have few intestinal CD4+ T cells (AGM) or that do not express CCR5 on their intestinal CD4+ T cells (SM). Evolutionary pressure from the virus may have changed fundamental aspects of the immune system in these species to evade AIDS.
Keywords: SIV; natural hosts ; T cell