Cleavage site compensatory substitutions partially restore fitness to simian immunodeficiency virus variants
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The human immunodeficiency virus is presently one of the most significant global health issues to date, with a disease burden that encumbers developing and developed nations alike. Although current antiretroviral therapy can help patients maintain undetectable levels of the virus throughout their bodies, once the treatment is ceased, the virus will rebound and disease progression continues. Thus, modalities to; 1- stop HIV transmission and spread, or 2- eradicate the virus once it is acquired are both urgently needed. In this project, we seek to evaluate and understand the impact of a candidate vaccine therapy that targets the HIV protease cleavage sites (PCS) on viral fitness. Vaccination with this modality in a monkey model induces mutations at virus regions that are intolerant to change, presumably affecting the "fitness" of viral strains recovered from vaccines. 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 results in improved maintenance of CD4+ T cells compared to unvaccinated controls (n=5). Furthermore, a correlation between the percentage of PCS mutations and reductions in viral load were seen. Our data indicate that the most common sites of mutation occur at two cleavage regions PCS2 and PCS12. We used site directed mutagenesis to introduce multiple PCS mutations into infectious clones of SIV. Our ongoing studies are evaluating the viral fitness of the SIV mutants in a cell lines and PBMC using competitive viral fitness assays. The data from these studies will help inform in the areas of vaccine and therapy development for HIV-1.