Research

We recently discovered that a previously unrecognized epigenetic modification called histone crotonylation is involved in an efficient transcription of HIV. The induction of crotonylation disrupts HIV latency. In combination with other latency reversal agents (LRAs), the disruption of HIV latency is highly achieved compared with a single LRA alone. We are particularly interested in whether crotonylation is distinct from acetylation and unique in the regulation of HIV transcription and latency. If so, what are the mechanisms that control such epigenetic regulation? We are also actively exploiting whether small molecules can be discovered to selectively target de-crotonylation over deacetylation. Such small molecules could be used for both HIV cure and cancer therapeutics.

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 immune cell models to deeply silence HIV proviruses, thereby preventing the virus from rebound. Efforts are also taken to discover the underlying mechanisms of how HIV reservoir achieves deep silencing.

We are interested in how tissue-resident HIV establishes its latent state of infection for its persistence. For example, how does the unique interaction among HIV, immune cells, vascular cells, and neuronal cells contribute to the initial seeding of HIV reservoirs in the CNS? Whether can we 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 PWH, and primary CNS cells directly isolated from fresh brains. Related to HIV brain reservoirs, we are developing new models of latency in microglia cells that are infected with HIV originating from PWH 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 the development of targeted therapeutics for the HIV cure in the CNS.