HIV infection provides a unique challenge to the immune system. CD4+ T cells are targets of infection, whereas effective anti-HIV CD4+ T-cell responses are essential for sustained viral control. There is increasing evidence of preferential depletion of certain subsets of CD4+ T cells. Studies of tissues have demonstrated preferential depletion of CD4+ T cells from gastrointestinal lymphoid tissue (GALT). Simian immunodeficiency virus infection of macaques results in extensive depletion of CD4+ memory T cells from GALT within weeks of infection. Other macaque studies suggest this rapid, profound depletion is generalized across all lymphoid tissue. Although these models provide insight into possible pathogenic processes, these results cannot be directly extrapolated to HIV infection in humans. Although there is depletion of CD4+ T cell memory cells early in HIV infection, the mechanism of this depletion appears to be related to increased cell turnover, chronicity of antigen exposure, and ineffective production of central memory CD4+ T cells rather than only direct cell depletion.