127 Making Sense of HIV Disease Pathogenesis Daniel Douek Vaccine Res Ctr, NIAID, NIH, DHHS, Bethesda, MD, USA

The mechanisms underlying CD4⁺ T-cell depletion in HIV infection are not well understood. Comparative studies of lymphoid tissues, where the vast majority of T cells reside, and peripheral blood can potentially illuminate the pathogenesis of HIV-associated disease. We have studied the effect of HIV infection on the activation and depletion of defined subsets of CD4⁺ and CD8⁺ T cells in blood, gastrointestinal (GI) tract, and lymph node (LN). We have also measured HIV-specific T-cell frequencies in LN and blood, and LN collagen deposition to define architectural changes associated with chronic inflammation. The major findings to emerge are: GI tract has the most substantial CD4⁺ T-cell depletion at all stages of HIV disease; this depletion occurs preferentially within CCR5⁺CD4⁺ T cells; HIV-associated immune activation results in abnormal accumulation of effector-type T cells within LN; HIV-specific T cells in LN do not account for all effector T cells; and T-cell activation in LN is associated with abnormal collagen deposition. Our findings define the nature and extent of CD4⁺ T-cell depletion in lymphoid tissue, and point to mechanisms of profound depletion of specific T-cell subsets related to elimination of CCR5⁺CD4⁺ T-cell targets and to disruption of T-cell homeostasis that accompanies chronic immune activation. Thus our data suggest that HIV-infection directly and indirectly causes damage to many immune compartments and a combination of such deleterious effects ultimately leads to immune failure and AIDS. Understanding the relative contribution of each of the factors that we have described can provide a rational framework upon which future therapeutic interventions can be based.