UCLA

CD8+ cytotoxic T lymphocytes (CTL) play an important role in HIV-1 infection. However, in most persons the HIV-1-specific CTL become dysfunctional. It has been suggested that anergy, a mechanism of T cell tolerance, may play a role in HIV-1-specific CTL dysfunction. Since HIV-1 is known to escape CTL recognition through mutation of epitopes to produce weak agonist altered peptide ligands (APL)—and anergy is thought to occur through suboptimal recognition—we hypothesized that weakly-recognized epitope variants may suboptimally stimulate the T-cell receptor (TCR) and trigger aberrant TCR signaling, leading to CTL anergy and enhanced viral persistence. We investigated weak agonist APL-mediated anergy as a potential mechanism of dysfunction in three HIV-1-specific CTL clones targeting three different epitopes. Clones were exposed to weakly-recognized epitope variants and screened for cytokine secretion, gene expression of markers of anergy and other forms of T cell dysfunction, and subsequent capacity to kill index peptide-presenting target cells in secondary challenge. Under those conditions, although suboptimal stimulation dampened cytokine secretion, we observed no patterns in gene expression profile consistent with anergy. Additionally, pre-exposure of CTL to weak agonist epitope variants had no discernable effect on their subsequent capacity to kill index epitope-bearing target cells. These data suggest that while weak agonist epitope variants evade CTL pressure through reduced recognition, their weak agonism does not appear to drive dysfunction of HIV-1-specific CTL, arguing against a role of APL-induced anergy in HIV-1-specific CTL dysfunction. However, under different experimental conditions, one HIV-1-specific CTL clone appeared to demonstrate varying degrees of reduced recognition of index epitope after pre-treatment with weak agonist APL stimulation. To try to reconcile these seemingly contradictory results, additional literature on the role of costimulation in both anergy and CD28- effector CTL is incorporated into the discussion. In Chapter 7, I propose a speculative model of how HIV-1-derived weak agonist APL, in conjunction with blockade of CD28-independent costimulatory pathways, may be able to cause HIV-1-specific CTL anergy in vivo. In Chapter 8, alternative approaches are suggested for possible future studies to resolve the confounding issues that still surround the field of APL-induced T cell anergy.