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.