Comparative fitness analysis of proteolytic cleavage site vaccine variants in simian immunodeficiency virus
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Over the past few decades, the human immunodeficiency virus and its progression to acquired immunodeficiency syndrome has become one of the most prominent global health issues. As the number of infected persons continues to grow, it is increasingly important to develop a protective vaccine to stop HIV transmission, and a cure for those already infected. Although current combination antiretroviral therapy can help patients maintain undetectable levels of the virus throughout their bodies, once the treatment is stopped, the virus will rebound. In this project, the effects of a vaccine therapy that targets the protease cleavage sites (PCS) of the HIV protease were evaluated in 16 Cynomolgus macaques. Preliminary results of the study show that in the vaccine group (n=11), a disruption to one or more of the HIV protease cleavage sites leads to a better maintenance of CD4+ T cells versus that in the control group (n=5). Furthermore, a correlation between the percentage of PCS mutations and viral load was also observed. Upon closer analysis, it was determined that the most common sites of mutation occur at PCS2 and PCS12. To assess the impact of these PCS mutations on viral fitness, we used site directed mutagenesis to introduce single amino acid mutations into a fully infectious SIV clone (SIVmac239). Ongoing studies include producing virus stocks of the SIVmac239 mutants (with multiple PCS mutations) and evaluating the viral fitness of the SIVmac239 clones in cell lines using growth competition assays. The data from this study and future studies will help provide information in the areas of vaccine and therapy development for HIV.