CD4 and HIV-1 infection: Based on our ex vivo modeling results, we theorize that mucosal pathogenesis may proceed in two phases during early HIV-1 infection: (1) there could be an ‘early phase’ of depletion, before intestinal barrier breakdown occurs, when depletion and inflammation are simultaneously driven by Caspase-1 mediated PCD in uninfected LP CD4+ T cells; and (2) a ‘late phase’ that is driven by the onset of microbial translocation, with exposure to microbial products resulting in increased HIV-1 replication and a larger role for apoptotic death of infected LP CD4+ T cells in ongoing depletion (Figure 7).