Loss of a Tyrosine-Dependent Trafficking Motif in the Simian Immunodeficiency Virus Envelope Cytoplasmic Tail Spares Mucosal CD4 Cells but Does Not Prevent Disease Progression

A hallmark of pathogenic simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) infections is the rapid and near-complete depletion of mucosal CD4 T lymphocytes from the gastrointestinal tract. Loss of these cells and dis-ruption of epithelial barrier function are associated with microbial translocation, which has been proposed to drive chronic sys-temic immune activation and disease progression. Here, we evaluate in rhesus macaques a novel attenuated variant of patho-genic SIVmac239, termedGY, which contains a deletion of a Tyr and a proximal Gly from a highly conserved YxxØ trafficking motif in the envelope cytoplasmic tail. Compared to SIVmac239,GY established a comparable acute peak of viremia but only transiently infected lamina propria and caused little or no acute depletion of mucosal CD4 T cells and no detectable microbial translocation. Nonetheless, these animals developed T-cell activation and declining peripheral blood CD4 T cells and ulti-mately progressed with clinical or pathological features of AIDS.GY-infected animals also showed no infection of macro-phages or central nervous system tissues even in late-stage disease. Although theGYmutation persisted, novel mutations evolved, including the formation of new YxxØmotifs in two of four animals. These findings indicate that disruption of this traf-ficking motif by theGYmutation leads to a striking alteration in anatomic distribution of virus with sparing of lamina propri