Recent studies suggest that the pathogenesis of HIV infection and AIDS involves two distinct phases. During acute infection, massive depletion of CD4+CCR5+ memory T cells within the mucosal-associated lymphoid tissue leads to major and potentially irreversible damage to CD4+ T-cell-mediated immune functions. The emergence of potent, but ultimately ineffective, cell-mediated and humoral responses to HIV leads to the chronic phase of infection, which is characterized by partial control of viral replication, chronic immune activation, progressive decline of the naïve and memory T-cell pool, and systemic CD4+ T-cell depletion. The identification of these two pathogenic phases of HIV infection could have important implications in terms of HIV therapy and vaccine development.