Liang Shan, Ph.D.

Assistant Professor
Internal Medicine
Infectious Diseases
Pathology and Immunology

Immunology Program
Molecular Microbiology and Microbial Pathogenesis Program

Research Abstract:

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. Our goal is to study 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

Selected Publications:

Gao H, Ozantürk AN, Wang Q, Harlan GH, Schmitz AJ, Presti RM, Deng K, Shan L. Evaluation of HIV-1 latency reversal and antibody-dependent viral clearance by quantification of singly spliced HIV-1 vpu/env mRNA. J Virol. 2021 Mar 24;. doi: 10.1128/JVI.02124-20.

Wang Q, Gao H, Clark KM, Mugisha CS, 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 Feb 4:eabe1707. doi: 10.1126/science.abe1707.

Shan L, Deng K, Gao H, Xing S, Capoferri AA, Durand CM, Rabi SA, Laird GM, Kim M, Hosmane NN, Yang HC, Zhang H, Margolick JB, Li L, Cai W, Ke R, Flavell RA, Siliciano JD, Siliciano RF. Transcriptional Reprogramming during Effector-to-Memory Transition Renders CD4+ T Cells Permissive for Latent HIV-1 Infection. Immunity. 2017 Oct 17;47(4):766-775.

Herndler-Brandstetter D, Shan L, Yao Y, Stecher C, Plajer V, Lietzenmayer M, Strowig T, de Zoete MR, Palm NW, Chen J, Blish CA, Frleta D, Gurer C, Macdonald LE, Murphy AJ, Yancopoulos GD, Montgomery RR, Flavell RA. Humanized mouse model supports development, function, and tissue residency of human natural killer cells. Proc Natl Acad Sci 2017 Oct 25.

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.

Shan, L., Deng K, Shroff NS, Durand CM, Rabi SA, Yang HC, Zhang H, Margolick JB, Blankson JN, Siliciano RF. Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity. 2012 Mar. 36(3): 491-501

Last Updated: 7/30/2021 4:56:26 PM

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