Effector CD8+ T cells in HIV infection are responsible for initial viremia control, however, HIV-specific CTL memory cells are lost during disease progression by an unknown mechanism. Our data show that HIV+ patients contain HIV-specific CD8+ CD28dim cells which die by costimulation via monocytes. In addition, we found that HIV causes over-expression of the CD28 ligands (CD80 and CD86) in vitro, inducing CD28 loss and apoptosis of CD8+ T cells. These observations suggest a fundamental mechanism whereby CD8+ T cells capable of becoming memory HIV-specific CTL could be selectively lost during disease progression. To study this hypothesis we propose three aims.
Aim 1 examines mechanisms for CD28 down-regulation and apoptosis. Using mixtures of CHO cell lines with defined levels of costimulatory ligands, CD80 or CD86, incubated with purified T cells, we will assess mechanisms responsible for Cd28 down-regulation and apoptosis. To examine the importance of HIV infection, we will mix autologous HIV-infected macrophages with T cells, examine CD80 and CD86 expression on the macrophages, as well as the effects of cell contact, soluble factors or cytokines released by the macrophages on CD28 down-regulation and apoptosis of the CD8+ T cells. Because little is known about molecular regulation of CD28 expression, Aim 2 will examine the down-regulation of the CD28 promoter by testing differential binding of NF-kBalpha and/or STAT-6 proteins, which will provide a molecular basis for prevention of CD28 loss.
Aim 3 will develop potential therapeutic methods to increase antigen-specific memory CD8+ T cells in HIV. Using alloantigen as a model, we will modulate costimulation, activation conditions, timing, strength of signals, and cytokines. The most promising methods to increase memory CD8+ T cells will be used with CD8+ T cells from HIV-infected patients. Because CD8+ T cells are important for HIV control, these studies are important for development of immune intervention strategies and for vaccine design.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (ZRG1-AARR-2 (01))
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Plaeger, Susan F
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Baylor College of Medicine
Schools of Medicine
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