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

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CD8+ T cells in human immunodeficiency virus (HIV)-infected people undergo significant alterations in phenotype and function during the disease. There is chronic activation as indicated by an increase in the expression of activation antigens such as CD38, DR, and CD57. The development of preactivated major histocompatibility complex (MHC)-restricted, HIV- specific cytotoxic T lymphocyte also is a unique feature of infection. The CD8+ T cells also are anergic and apoptotic in vitro and have reduced cloning efficiency. Late in infection, HIV-specific CTL function is lost which may be responsible for HIV disease progression. Our hypothesis is that many of these observations are related directly to the loss of surface expression of the important T cell activation molecule, CD28. The interaction of CD28 with ligands on antigen-presenting cells is known to be crucial for T cell activation. We propose to address the importance of CD28 function in HIV infection by three specific aims. Specific Aim 1 is to perform a cross-sectional study of HIV+ people early after infection, during the asymptomatic period, in patients with AIDS, and in long-term survivors. We will determine the timing of CD28 loss on CD8+ T cells as a function of disease status, immune function, virologic status, and susceptibility of cells to apoptosis. These studies will determine the clinical significance of our observation and will ask whether the CD8 cells are affected early in infection or whether intact CD28 expression in a determinant of long-term survival. Specific Aim 2 is to perform a longitudinal study to address whether the loss of HIV-specific CTL function late in infection is due to loss of CD28 expression, associated with viremia, development of anergy, apoptosis, and clinical progression. This study addresses whether loss of containment of HIV by cytotoxic T cells is due to loss of CD28 expression. Specific Aim 3 examines a specific mechanism of CD28 gene regulation. A major hypothesis of HIV pathogenesis is that a T-1 to T-2 switch occurs in cytokine production as the disease progresses. No one has addressed the ramifications of the hypothesis on development of CD8+ T cells or their function. Preliminary data indicate that a T-2 cytokine environment causes CD28 down-regulation on CD8+ T cells from control individuals. We propose to test the hypothesis that CD28 gene transcription is negatively regulated by T-2 cytokines via a reduction in NF-kB activity. Thus, these studies will explore the molecular regulation of CD28 expression. This proposal has significance for vaccine design and gene therapy approaches because understanding the role of CD28 in containment of HIV by CD8+ T cells may lead to augmentation or intervention.