Current antiretroviral therapy (ART) is effective in the suppression of HIV replication but failed to eliminate latent HIV reservoirs. Our lab aims to discover the molecular mechanisms how HIV transcription machinery is regulated during active HIV transcription and during the establishment of latency. The ultimate goal is to translate our understanding of transcription and latency of HIV into therapeutic interventions.
Epigenetic Regulation of HIV Transcription and Latency
We recently discovered that a previously unrecognized epigenetic modification called histone crotonylation is involved in an efficient transcription of HIV. The induction of crotonylation disrupted HIV latency. In combination with other latency reversal agents (LRAs), the disruption of HIV latency is highly achieved compared with a single LRA. We are particularly interested whether crotonylation is distinct from acetylation and unique in the regulation of HIV transcription and latency and the underlying mechanisms.
Development of HIV cure strategies
We recently established a novel HIV deep latency model in which not only deep silencing of HIV can be induced but also sustained. We are actively investigating the molecular mechanisms underlying this “true” state of deep latency and extending it to patient models to deeply silence HIV proviruses and prevent viral rebound. Efforts are also taken to discover the mechanisms of stable HIV reservoir so that the stability of such a reservoir can be targeted by direct killing for the eradication of HIV.
HIV Tissue Reservoirs
We are interested in how tissue resident HIV achieves its latent state of infection for its persistence. For example, how the unique interaction among HIV, immune cells, vascular cells, and neuronal cells contributes to the initial seeding of HIV reservoirs in the CNS, and whether we can target the unique viral infection and latency signaling pathways to attack HIV reservoirs in the CNS, thereby controlling HIV infection and HIV-associated neurocognitive disorders (HAND). We are studying these in the HIV-infected rhesus macaques, brain tissues from PLWH, and primary CNS cells directly isolated from fresh patient brains. Related to HIV brain reservoirs, we are developing new models of latency in microglia cells that infected with HIV originated from patient brain myeloid cells, including HIV latently infected primary microglia and native microglia-containing organoid model of human mini-brain. These models are useful for us to understand the underlying mechanisms of HIV reservoirs in the CNS and development of targeted therapeutics for the HIV cure in the CNS.
Our lab is actively supported by Qura Therapeutics, UNC Center for AIDS Research, NIMH and CARE Program.