HIV-1 Gene Suppression by CD8+ T Cells

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DESCRIPTION (provided by applicant): Elimination of HIV replication in vivo has not been achieved to date because HIV establishes and persists in a latent state in host cells. Although attempts have been made to activate and eliminate these reservoirs, the most potent antiretroviral regimens in use today do not eradicate HIV from its latent state. For HIV, it is not known how provirus latency is induced and maintained in vivo. A better understanding of whether host immune responses are involved in HIV latency is needed. We have determined that noncytolytic CD8 suppression occurs during the time of virus gene expression and inhibits the initiation of virus transcription. We now have evidence that the same epigenetic changes that occur during provirus latency also occur as a result of noncytolytic CD8 suppression. We propose to build upon this novel finding to determine if noncytolytic CD8 suppression is directly involved in HIV latency. The molecular events of chromatin remodeling required for transcriptional regulation will be examined to determine the linkage between noncytolytic CD8 suppression and provirus latency. Analyses of chimeras of genetically related pair of viruses with opposing sensitivities to CD8 suppression will determine if the resistant virus phenotype results from molecular changes required for latency. The results from this study can provide a better understanding of the current limitations of antiretrovirals, in addition to immediately altering candidate HIV vaccine design and evaluation. Potential implications of this work are that noncytolytic CD8 T cells would be of benefit for disease-modifying vaccine strategies aimed to reduce peak viremia and set point, but would not be of benefit for preventative vaccine strategies. This study has two specific aims: 1. Determine if noncytolytic CD8+ T cell mediated HIV suppression causes HIV latency. 2. Identify the viral genetic changes linked to noncytolytic CD8 resistance and determine the role of latency. PUBLIC HEALTH RELEVANCE: Noncytolytic CD8 T cell mediated suppression plays an important role in viral control in natural HIV infection and thus could be an important immune response to elicit by vaccination. Conversely, the elicitation of this immune response may be undesirable if a protective vaccination strategy is the goal. The results from this study will determine if induction of noncytolytic CD8 T cells would be beneficial in a protective vaccination strategy or whether it should be restricted to disease-modifying vaccine strategies.