Dimapasoc, Melanie
Melanie is in the Immunity, Microbes, & Molecular Pathogenesis home area of the MBIDP. She joined the CMB training program in 2018. Her research mentor is Dr. Jerome Zack. She received a B.S. degree in Biology (Physiology) from San Francisco State University.
Mentor: Dr. Jerome Zack
Despite advances in the development of antiretroviral therapy (ART), HIV remains a global epidemic. ART suppresses HIV to undetectable levels; however, a subset of long-lived, quiescent memory CD4+ T cells harboring integrated, but transcriptionally inactive, provirus persists and can lead to viral rebound upon interruption of therapy. Moreover, there are several limitations to lifelong ART, including the development of drug-resistant virus and inadequate access to treatment, especially in developing countries. These limitations underscore the need to develop more effective therapeutic approaches. Current HIV cure strategies focus on eliminating or reducing the size of the latent reservoir through a “kick and kill” approach in which latency reversal agents (LRA) that activate HIV transcription coax the virus out of dormancy where it can be eliminated via virus-induced cytopathic effects, immune clearance, apoptosis or antiviral therapies. Several classes of LRAs have been tested in vitro and ex vivo and a few candidates have advanced to early-phase clinical trials. Two of the most promising classes of LRAs being tested in clinical trials are histone deacetylase inhibitors (HDACi) and protein kinase C (PKC) modulators.
The goal of my project is to optimize HIV latency reactivation in vivo through the co-administration of PKC modulators and HDAC inhibitors in a humanized mouse model. We and others have shown that some PKC activators and HDACi exhibit a greater than additive degree of HIV latency reactivation in vitro when used in combination rather than individually. Whether the same is true in vivo remains untested. I will infect NSG-BLT mice with barcoded HIV, treat with ART while monitoring viral load, then treat with LRAs and measure the degree of latency reactivation. Using flow cytometry, I will measure acetylated histone H3 and CD69 expression to determine the cellular effects of HDACis and PKC modulators, respectively. The effects on HIV latency will be monitored in two ways: 1) expression level of the HA epitope tag when our reporter virus is being actively expressed; 2) determination of the diversity of the HIV swarm by deep sequencing. Using similar methods, I will also test whether multiple rounds of latency reactivation can completely eliminate the viral reservoir. Successful completion of this project may have a significant impact on HIV therapy, possibly eliminating the necessity for life-long treatment through the reduction or eradication of the HIV latent reservoir.
