Homeostatic Cytokines Induce CD4 Downregulation in African Green Monkeys Independent of Antigen Exposure to Generate SIV-resistant CD8aa T Cells.

Journal of virology

PubMedID: 24991011

Perkins MR, Briant JA, Calantone N, Whitted S, Vinton CL, Klatt NR, Ourmanov I, Ortiz AM, Hirsch VM, Brenchley JM. Homeostatic Cytokines Induce CD4 Downregulation in African Green Monkeys Independent of Antigen Exposure to Generate SIV-resistant CD8aa T Cells. J Virol. 2014;.
African green monkeys (genus Chlorocebus) are a natural host of simian immunodeficiency virus (SIVagm). As they do not develop simian AIDS, there is great interest in understanding how this species has evolved to avoid immunodeficiency. Adult African green monkeys naturally have low numbers of CD4 T cells and a large population of MHC Class II-restricted CD8a(dim) T cells that are generated through CD4 downregulation in CD4(+) T cells. Mechanisms that drive this process of CD4 downregulation are unknown. Here we show that juvenile AGMs accelerate CD4 to CD8aa conversion upon SIV infection and avoid progression to AIDS. The CD4 downregulation induced by SIV infection is not limited to SIV-specific T cells, and vaccination of an adult AGM who had a negligible number of CD4 T cells demonstrated that CD4 downregulation can occur without antigenic exposure. Finally, we show that the T cell homeostatic cytokines IL-2, IL-7 and IL-15 can induce CD4 downregulation in vitro. These data identify a mechanism that allows AGMs to generate a large, diverse population of T cells that perform CD4 T cell functions but are resistant to SIV infection. A better understanding of this mechanism may allow the development of treatments to induce protective CD4 downregulation in humans.IMPORTANCE
Many African primate species are naturally infected with simian immunodeficiency virus (SIV). African green monkeys, one natural host species, avoid simian AIDS by creating a population of T cells that lack CD4, the HIV/SIV receptor, that are therefore resistant to infection. However, these T cells maintain properties of CD4(+) T cells even after receptor downregulation, and preserve immune function. Here we show that juvenile AGMs, who have not undergone extensive CD4 downregulation, accelerate this process upon SIV infection. Furthermore, we show that in vivo, CD4 downregulation doesn't occur exclusively in antigen-experienced T cells. Finally, we show that the cytokines IL-2, IL-7 and IL-15, which induce homeostatic T cell proliferation, lead to CD4 downregulation in vitro and therefore can provide signals that lead to antigen-independent CD4 downregulation. These results suggest that if a similar process of CD4 downregulation could be induced in humans, it could theoretically provide a cure for AIDS.