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. 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. Shans’ lab studies immunobiology of HIV infection and train human immune system to better control and/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 and survival of human innate immune cells in the mouse system. These novel humanized mouse models support functional development of human macrophage and NK cell. Using these mouse models, we focus on the following topics:1) control of HIV-1 infection by NK cells; 2) 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.

· Unanue Prize，Washington University in St. Louis, 2024

· Andrew and Virginia Craig Faculty Award, Washington University in St. Louis,  2022

· Junior Investigator Award,  Association of Chinese Virologists in America, 2022

· K99 Award, NIAID, NIH, 2016

1.Pal. P, Gao S, Gao H, Cella M, Wang Q, Shan L. Establishment of a Reverse Genetics System for Studying Human Immune Functions in Mice. Science Advances. 2025 Jul 11;11(28):eadu1561.

2.Wang Q, Clark KM, Tiwari R, Raju N, Tharp GK, Rogers J, Harris AR, Raveendran M, Bosinger SE, Burdo TH, Silvestri G, Shan L. The CARD8 Inflammasome Dictates HIV/SIV Pathogenesis and Disease Progression. Cell. 2024 Feb 29;187(5):1223-1237.e16.

3.Clark KM, Kim JG, Wang Q, Gao H, Presti RM, Shan L. Chemical inhibition of DPP9 sensitizes the CARD8 inflammasome in HIV-1-infected cells. Nature Chemical Biology. 2023 Apr;19(4):431-439. doi: 10.1038/s41589-022-01182-5.

4.Sungur CM, Wang Q, Ozanturk AN, Gao H, Schmitz AJ, Cella M, Yokoyama WM^#, Shan L^#. Human NK cells confer protection against HIV-1 infection in humanized mice. J Clin Invest. 2022 Dec15;132(24):e162694. doi: 10.1172/JCI162694. ^#co-corresponding author

5.Wang Q, Gao H, Clark KM, Shema Mugisha C, Davis K, Tang JP, Harlan GH, DeSelm CJ, Presti RM, Kutluay SB, Shan L. CARD8 is an inflammasome sensor for HIV-1 protease activity. Science. 2021 Mar 19;371(6535):eabe1707.

6.Song Y*, Shan L*, ^#, Gbyli R*, Liu W, Strowig T, Patel A, Fu X, Wang X, Xu ML, Gao Y, Qin A, Bruscia EM, Tebaldi T, Biancon G, Mamillapalli P, Urbonas D, Eynon E, Gonzalez DG, Chen J, Krause DS, Alderman J, Halene S^#, Flavell RA^#. Combined liver–cytokine humanization comes to the rescue of circulating human red blood cells. Science. 2021 Mar 5;371(6533):1019-1025. * co-first author. ^#co-corresponding author

7.Deng K, Pertea M, Rongvaux A, Wang L, Durand CM, Bhiaur G, Lai J, McHugh HL, Hao H, Zhang H, Margolick JB, Gurer C, Murphy AJ, Valenzuela DM, Yancopoulos GD, Deeks SG, Strowig T, Kumar P, Siliciano JD, Salzberg SL, Flavell RA^#, Shan L^#, Siliciano RF^#. Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations. Nature. 2015 Jan 15;517(7534):381-5. ^#co-corresponding author

Our lab is always looking for exceptional postdoctoral researchers and research assistants who are eager to further their training. We welcome talented individuals interested in advancing research in HIV immunology and related fields.