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HIV infection in humans and experimental SIV infection in rhesus macaques leads to the loss of recall antigen responses, immunological anergy in CD4 T cells and AIDS. In contrast, natural infection in sooty mangabeys with SIV does not lead to disease despite high viral loads accompanied by resistance of their CD4 T cells to undergo immunological anergy. The objective of the study was to further elucidate the mechanisms that contribute to anergy resistance in CD4 T cells from sooty mangabeys and identify whether the anergy resistance is a function of a specific subset or the entire cell population.Susceptibility or resistance to anergy was analyzed in antigen specific and defined CD4 T cell subsets from peripheral blood of sooty mangabeys and rhesus macaques by using an in vitro anergy inducing protocol; expression of the anergy associated gene GRAIL was measured.Antigen specific CD4 T cells from SIV disease resistant sooty mangabey are relatively resistant to the development of anergy. This resistance is associated with a lack of an upregulation of GRAIL. Conversely, rhesus macaque CD4 T cells are sensitive to anergy induction associated with upregulation of GRAIL. Furthermore the anergy resistant phenotype of sooty mangabey CD4 T cells predominantly resides in central memory cells defined either as CD4+CD45RA−CD62L+ or CD4+CD28+CD95+CCR7+.The maintenance of recall responses in sooty mangabeys is associated with the resistance of central memory CD4 T cells to the induction of anergy which may represent an important mechanism underlying SIV disease resistance in this species.