Despite the successful development of antiretroviral therapies (ART), the long-awaited cure for HIV has still not
been discovered. The virus integrates into DNA of tissues throughout the body and becomes latent after
institution of ART. Persons receiving ART cannot discontinue their medications, as in most cases the virus will
simply rebound upon ART cessation. One approach to finding a cure is to eliminate the reservoir by bringing
the virus out of latency so that infected cells might be killed by ART or the host immune system. Epigenetic
mechanisms are believed to play an important role in retroviral latency, yet little is known about the epigenetic
markers associated with the latent reservoir for HIV. Surprisingly, even less has been published for SIV, where
access to tissues and time lines of infection are better characterized and controlled. While SIV-infected
macaques serve as a model for human HIV infection, there is no knowledge of whether SIV and HIV
epigenetics have any similarity. To develop successful therapeutics that target epigenetic mechanisms of HIV
latency, we must first identify these mechanisms and whether animal models will be suitable to test them.
The proposed project will characterize the proportion of proviruses located in open chromatin and containing
repressive epigenetic marks both during ART and after discontinuation of ART in HIV-infected humans and
SIV-infected macaques. Further, I will use these parameters to evaluate the association with the size of the
reservoir, cell-associated RNA, and viral rebound after ART cessation in both peripheral T cells and brain,
which is a poorly characterized reservoir tissue. These studies will allow me to conclude what role repressive
epigenetic marks play in proviral latency, and whether these mechanisms differ between tissues, and species.
Importantly, this project will support my development as an independent researcher with expertise in clinical
retroviral epigenetics and comparative research. The proposed training will provide me with exposure to trial
design and analysis methods, including biostatistics and bioinformatics. These methods are critical to my
career development, as we are now heavily reliant on next-generation sequencing technologies, and the
comparative studies I wish to pursue will require an understanding of statistical methods for study design and
data analysis. Finally, this project will build upon my background in comparative medicine, retrovirology, and
epigenetics. I will receive training in 1) clinical epigenetics techniques 2) biostatistics and bioinformatics 3) non-
human primate (NHP) procedures and NHP animal welfare 4) ethical conduct of HIV research and 5)
professional development, including grantsmanship, building collaborations, and reporting research findings.
My mentoring team includes an excellent track records in all proposed areas of training, including retrovirology,
epigenetics, biostatistics, bioinformatics, and non-human primate SIV research. This proposal builds upon
previous NIH funded research and complements current NIH funded projects.