HIV-1 has high mutation rates and exists as mutant swarms within the host. Rapid evolution allows the virus to outpace the host immune system, leading to viral persistence. In patients who received antiretroviral therapy (ART), HIV-1 persists in a latent form primarily in quiescent CD4+ T cells and possibly tissue macrophages. The “shock and kill” strategy to purge HIV-1 latent reservoirs involve reactivation of latent viruses by latency reversal agents (LRAs) and elimination of infected cells by viral-specific host immune responses. Immune escape variants achieved in the latent viral reservoirs present one of the major obstacles to HIV-1 eradication. To date, no broadly applicable strategy has been developed to prevent or eradicate HIV-1 infection. Our goal is to study immunobiology of HIV infection and train human immune system to better control or clear HIV-1 infection.
1. The CARD8 inflammasome
We recently reported that the CARD8 is an inflammasome sensor for HIV-1 protease (PR) activity. CARD8 can be activated via direct proteolysis of its N-terminus by HIV PR, creating an unstable neo-N-terminus. This, in turn, triggers proteasome degradation to release its bioactive C-terminus, leading to caspase 1 activation and pyroptosis. HIV PR mediates virion maturation. HIV-1 evades CARD8 sensing in host cells because PR remains inactive as a subunit of Gag–Pol polyprotein prior to viral budding. A class of anti-HIV drugs named NNRTI can activate HIV PR through binding to the Gag–Pol. Treating HIV-infected macrophages and CD4+ T cells with NNRTIs leads to rapid pyroptotic cell death. This strategy clears HIV reservoirs in patient blood T cells after virus reactivation. Currently, we focus on the molecular basis of CARD8 and HIV PR interaction, as well as development of CARD8-based HIV cure strategies.
2. Humanized mouse models for HIV-1 infection and immunotherapy
Our research is hampered by the limited ability to investigate HIV-1 infection in tissues and the lack of understanding of antiviral immune responses in vivo. We have generated novel mouse models that contain multiple human gene knock-ins to improve human hematopoiesis and maturation of human immune cells in the mouse system. Compared to commonly used humanized mouse models, our models support functional development of human macrophages, NK cells, and memory T cells in tissues, which allow us to study the following topics: 1) control of HIV-1 infection by NK cells; 2) roles of tissue macrophages in HIV-1 infection, latent viral reservoirs, and innate immune sensing; 3) antibody Fc-receptor functions; 4) transcriptional and metabolic reprogramming of HIV-1 reservoirs in CD4+ T cells.