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Center for Nonlinear Studies |
In human (HIV) and pathogenic simian immunodeficiency virus (SIV) infection, CD4+/CCR5+ T-cells are targeted during acute infection and rapidly depleted, particularly at mucosal sites. This depletion is linked to a loss of epithelial barrier function, microbial translocation, and sustained immune activation that is associated with defects in adaptive immune functions and ultimately a loss of CD4+ T-cell regenerative capacity and AIDS. An invariant feature of HIV and SIV pathogenesis that underlies these events is CD4 tropism, mediated by a highly conserved CD4 binding site on the gp120 envelope glycoprotein (Env). Using the pathogenic SIV molecular clone SIVmac239, our laboratory has developed two models in which targeted mutations in the viral Env produce novel alterations in viral/host interactions. In one, the “∆GY model,†a deletion of two amino acids (Gly and Tyr) within a highly conserved trafficking motif in the Env cytoplasmic tail results in a virus that replicates acutely to wildtype levels but spares gut CD4+ T-cell and fails to cause microbial translocation. In pigtail macaques this virus is rapidly controlled by host immune cellular immune responses and animals subsequently are able to resist or control challenges with pathogenic homologous and heterologous SIV isolates. In the second, the “iMac model,†a CD4-independent variant of SIVmac239 was derived and further engineered to be able to infect macaque lymphocytes in the absence of CD4 binding. As the first non-CD4 tropic SIV, this virus is currently being evaluated in non-human primates to assess the consequences of CD4+ T-cell sparing in SIV infection. Both the ∆GY and the iMac models will be presented, and their utility in studying correlates of viral control and protection in pathogenesis and vaccine studies discussed.
Host: Gnana Ganakaran