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Membrane metalloprotease TRABD2A restricts HIV-1 progeny production in resting CD4+ T cells by degrading viral Gag polyprotein

Nature Immunology volume 20, pages 711–723 (2019)Cite this article

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Abstract

Resting CD4+ T cells are highly resistant to the production of human immunodeficiency virus type 1 (HIV-1). However, the mechanism by which resting CD4+ T cells restrict such production in the late viral replication phase of infection has remained unclear. In this study, we found that the cell membrane metalloprotease TRAB domain-containing protein 2A (TRABD2A) inhibited this production in resting CD4+ T cells by degrading the virion structural precursor polyprotein Gag at the plasma membrane. Depletion or inhibition of metalloprotease activity by TRABD2A profoundly enhanced HIV-1 production in resting CD4+ T cells. TRABD2A expression was much higher in resting CD4+ T cells than in activated CD4+ T cells and was considerably reduced by T cell activation. Moreover, reexpressing TRABD2A reinforced the resistance of activated CD4+ T cells to the production of HIV-1 progeny. Collectively, these results elucidate the molecular mechanism employed by resting CD4+ T cells to potently restrict the assembly and production of HIV-1 progeny.

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Fig. 1: TRABD2A is mainly expressed in resting CD4+ T cells.
Fig. 2: TRABD2A expression is inversely correlated with plasma viral loads in vivo.
Fig. 3: Identification of TRABD2A as a potent restriction factor for HIV-1 infection.
Fig. 4: TRABD2A requires metallic cations to restrict HIV-1 infection.
Fig. 5: TRABD2A degrades the HIV-1 Gag polyprotein precursor at the plasma membrane.
Fig. 6: TRABD2A metalloprotease activity restricts HIV-1 progeny production in resting CD4+ T cells.
Fig. 7: Depletion of SAMHD1 promotes HIV-1 progeny production in resting CD4+ T cells only when TRABD2A protease is inhibited.
Fig. 8: TRABD2A restricts HIV-1 production ex vivo.

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Data availability

RNA-seq data generated for this study (Fig. 1b) have been deposited in the Sequence Read Archive under accession code PRJNA522052.

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Acknowledgements

We thank all our laboratory members for contributing to this study. We also thank S. Yu, Y. Xiong, J. Ouyang and R. Wang for their technical support. This study was supported by the Mega Projects of National Science Research for the 13th Five-Year Plan (grant no. 2017ZX10201101), Development Plan of Innovative Group of the Ministry of Education 2016 (grant no. IRT_16R70) and the National Natural Science Foundation of China (grant no. 81273238).

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Authors and Affiliations

  1. Key Laboratory of AIDS Immunology of National Health and Family Planning Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang, China

    Guoxin Liang, Li Zhao, Wenqing Geng, Mei Liu, Jinxiu Dong, Haibo Ding, Hong Sun & Hong Shang

  2. Key Laboratory of AIDS Immunology, Chinese Academy of Medical Sciences, Shenyang, China

    Guoxin Liang, Li Zhao, Wenqing Geng, Mei Liu, Jinxiu Dong, Haibo Ding, Hong Sun & Hong Shang

  3. The Core Laboratory for Public Health Science and Practice, The First Affiliated Hospital, China Medical University, Shenyang, China

    Ying Qiao & Xiaowei Zhang

  4. Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China

    Hong Shang

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Contributions

G.L. conceived and directed the whole research project. Y.Q., W.G., L.Z., M.L., J.D., X.Z., H.D. and H. Sun performed the experiments and analyzed the data. W.G., H. Sun and H. Shang provided intellectual advice on the experimental design. G.L. wrote the manuscript.

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Correspondence to Guoxin Liang or Hong Shang.

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Liang, G., Zhao, L., Qiao, Y. et al. Membrane metalloprotease TRABD2A restricts HIV-1 progeny production in resting CD4+ T cells by degrading viral Gag polyprotein. Nat Immunol 20, 711–723 (2019). https://doi.org/10.1038/s41590-019-0385-2

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