Down-regulation of CD4 by memory CD4(+) T cells in vivo renders African green monkeys resistant to progressive SIVagm infection

African green monkeys (genus Chlorocebus) can be infected with SIVagm, but do not develop AIDS. This natural host of SIV, like sooty mangabeys, maintains high levels of SIV replication but has evolved to avoid immunodeficiency. Elucidating the mechanisms that allow the natural hosts to co-exist with SIV without overt disease may provide crucial information to understand AIDS pathogenesis. Here we show: (1) many CD4(+) T cells from African green monkeys down-regulate CD4 in vivo as they enter the memory pool, (2) down regulation of CD4 by memory T cells is independent of SIV infection, (3) the CD4(−) memory T cells maintain functions which are normally attributed to CD4 T cells including production of IL-2, production of IL-17, expression of FoxP3 and expression of CD40L (4) loss of CD4 expression protects these T cells from infection by SIVagm in vivo, and (5) these CD4(−) T cells can maintain MHC-II restriction. These data demonstrate that the absence of SIV-induced disease progression in natural hosts species may be partially explained by preservation of a subset of T cells that maintain CD4 T cell function while being resistant to SIV-infection in vivo.