Comparative Retroviral Epigenomics

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Abstract Although effective antiretroviral therapies (ART) have been developed for HIV, a cure has remained elusive even after more than three decades. Because the virus integrates into host DNA and can silence itself with or without ART through harnessing host epigenetic mechanisms, it is highly effective at masking its presence from the immune system, making its clearance difficult. Two strategies have been proposed to attempt to cure the virus once and for all, both dependent upon epigenetic modulation. The first proposes to 'kick and kill' the virus by reversing silencing modifications in order to make the virus visible to the immune system. The second strategy proposes to 'block and lock' the virus by introducing permanent epigenetic silencing, resulting in a functional clinical cure. Both strategies require a far more exhaustive understanding of the epigenetic silencing modifications exploited by the HIV provirus. The parent K01 proposal sought to characterize more specifically the role of two known modifications (DNA methylation and H3K27me3) from clinical samples of patients with HIV, and to compare them to rhesus macaques with SIV, which are considered to be the best animal model for HIV infection, as any and all epigenetic targets will likely be tested on them first. The COVID-19 pandemic hindered scientific research across the globe and impacted new investigators heavily. This original K01 proposal was no exception, as the primary investigator on this grant was substantially impacted by the pandemic. Therefore, this supplement seeks to overcome the barriers introduced by the pandemic in order to finish this important work examining proviral silencing in the brain. The brain is a particularly important reservoir tissue, as the virus is known to sequester itself at this site and appears to play a role in the development of cognitive impairment in people with HIV (PWH). Therefore, we are evaluating whether the same mechanisms are at play for SIV in the brains of rhesus macaques.