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Recent work in pathogenic simian immunodeficiency (SIV) infection of Asian macaques and in natural, nonpathogenic SIV infections of African nonhuman primate species has demonstrated that persistent activation has profound effects on CD4+ memory T-cell proliferation, differentiation and survival. Disease progression in pathogenic infection has been closely linked to these dynamics, reflecting a complex interplay of virus-mediated killing, the effects of systemic activation and host regenerative mechanisms. We review these recent advances.Massive depletion of CD4+ effector-memory T cells invariably occurs during acute CCR5-tropic SIV infection, but is initially stabilized by new production of these cells from spared central memory precursors above the threshold required to maintain clinical immune competence. In pathogenic (but not natural, apathogenic) infections, a persistent state of immune activation, characterized by multiple, recurrent bursts of lymphocyte proliferation, differentiation, migration, death and functional modification of ‘resting’ cells, is associated with progressive depletion of central memory CD4+ T cells, and ultimately, a collapse of effector site CD4+ memory populations that is closely associated with overt immune deficiency.The importance of maintaining the regenerative capacity of the central-memory compartment of CD4+ T cells is increasingly evident. Defining the physiologic and molecular mechanisms responsible for instability of the CD4+ central-memory T cell pool could enable new immunotherapeutic interventions.