ANERGY, APOPTOSIS AND CD28 IN CD8+ T CELLS DURING AIDS

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EXCEED THE SPACE PROVIDED. CD8 ¿ T cells are essential for HIV clearance early in infection. However, in most people, CD8 + memory cells are defective or die at an increased rate. Our recent work shows that patient monocytcs kill CD8 + T cells from both patients and controls and that control monocytes kill patient CD8 ¿ T cells, suggesting that the death of CD8 + T cells in HIV is NOT antigen specific. Other work shows that both TNF-alpha and CD28 agonism (strong B7 signals, CD80, or agonistic CD28 Ab) downregulat¿ CD28 expression and can induce death associated with sustained c-tel translocation. Because mTNF is upregulated by CD28 agonism, a plausible hypothesis for CD28 agonistic death is induction via TNFR1/TNFR2 ligation, leading to NFKB activation. Aim 1 will therefore examine mechanisms of CD28 agonistic signaling that leads to cell death. Because CD28 is differentially glycosylated on T cells that respond to CD28 agonism by dying, and the location of CD28 on the surface of ceUs that die is altered, Aim 2 will examine mechanisms for alteration of CD28 cell surface conformation, including differential glycosylation characteristics and activation-induced changes of CD28. We will characterize sugars on CD28, mutate the five glycosylation sites in CD28, and study glycosylation patterns and location of CD28 before and after activation ofT cells. Patient and control T cells will be compared as to differential CD28 glycosylation or location patterns related to the ability to respond to strong B7 signals. Because a key problem in HIV is the development of non-functional CD28" cells, Aim 3 will use alloantigen as antigen and vary the type of antigen presenting cells, cytokines, costimulatory molecules, and investigate the role of CD4 + T cells to develop ways to enhance CD8 + T cell viability. The most promising methods that increase CD28 + memory CD8 + T cells wiU be used with CD8 + cells from HIV + patients. These experiments are important for HIV control by therapeutic vaccines because of strategies needed to enhance CD28 expression and survival of CD8 + T cells for enhancement of their long-term capabilities in vivo. PERFORMANCE SITE ========================================Section End===========================================