Research

Previously, we discovered that a new epigenetic modification called histone crotonylation is involved in the efficient transcription of HIV (Jiang G et al., JCI 2018). The induction of crotonylation by NaCr disrupts latent HIV. Conversely, suppressing crotonylation tends to inhibit HIV transcription. Our recent studies support that (de)crotonylation is distinct from (de)acetylation and unique in regulating HIV latency (Li X et al., Sci Adv 2026). However, it remains less determined what mechanisms control such epigenetic regulation, independent of many other acylations, even though they are controlled by the same enzymes. We are also actively exploring whether small molecules can be discovered to specifically target de-crotonylation, and if defined, whether such small molecules could be used for the study of HIV cure, and what the structural basis is for such a mechanism.

We are interested in how HIV establishes latency in the CNS to persist in the brain resident immune cells and the impact of HIV persistence in the CNS (Tang Y et al., JCI 2023; Prates GS et al., Emerg Microbes Infect. 2026). For example, how does the unique interaction among HIV, immune cells, neurovascular cells, and neuronal cells contribute to the initial seeding of HIV reservoirs in the CNS? How does neuroinflammation persist in the CNS? Is neuroinflammation associated with neuronal injury (Tang Y et al., PLoS Pathog 2025; Apoliano CF et al., AIDS 2026)? Can we target the unique viral latency signaling pathways to attack HIV reservoirs in the CNS, thereby controlling HIV infection and HIV-associated neurocognitive injury? We are studying these in the brains of SIV-infected rhesus macaques, in brain tissue from PWH, and in primary CNS cells directly isolated from fresh brains. We are developing new models of latency in microglia that are infected with HIV originating from PWH brain myeloid cells, including HIV latently infected primary microglia and a native microglia-containing organoid model of human mini-brains.

We recently established a novel HIV deep latency model in which not only deep silencing of HIV can be induced but also sustained (Elsheikh MM et al. EBiomedicine 2019). 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 rebounding. Efforts are also taken to discover the underlying mechanisms of how the HIV reservoir achieves deep silencing. Meanwhile, other tools are also being studied to eradicate latent HIV reservoirs in T cells and non-T cells, including direct killing and “kick and kill” (Jiang G et al., PLoS Pathog 2015; Jiang G et al., JCI Insight 2019; Li D et al., iScience 2022;Li X et al., Sci Adv 2026). Consequently, a few animal studies are ongoing for the eradication of HIV in vivo.