Vpr counteracts the restriction of LAPTM5 to promote HIV-1 infection in macrophages

Li Zhao, Shumei Wang, Meng Xu, Yang He, Xiaowei Zhang, Ying Xiong, Hong Sun, Haibo Ding, Wenqing Geng, Hong Shang and Guoxin Liang ()
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Li Zhao: Key Laboratory of AIDS Immunology of Ministry of Health, The First Affiliated Hospital, China Medical University
Shumei Wang: Key Laboratory of AIDS Immunology of Ministry of Health, The First Affiliated Hospital, China Medical University
Meng Xu: Research Institute for Cancer Therapy, The First Affiliated Hospital, China Medical University
Yang He: Research Institute for Cancer Therapy, The First Affiliated Hospital, China Medical University
Xiaowei Zhang: Key Laboratory of AIDS Immunology of Ministry of Health, The First Affiliated Hospital, China Medical University
Ying Xiong: Key Laboratory of AIDS Immunology of Ministry of Health, The First Affiliated Hospital, China Medical University
Hong Sun: Key Laboratory of AIDS Immunology of Ministry of Health, The First Affiliated Hospital, China Medical University
Haibo Ding: Key Laboratory of AIDS Immunology of Ministry of Health, The First Affiliated Hospital, China Medical University
Wenqing Geng: Key Laboratory of AIDS Immunology of Ministry of Health, The First Affiliated Hospital, China Medical University
Hong Shang: Key Laboratory of AIDS Immunology of Ministry of Health, The First Affiliated Hospital, China Medical University
Guoxin Liang: Key Laboratory of AIDS Immunology of Ministry of Health, The First Affiliated Hospital, China Medical University

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract The HIV-1 accessory proteins Vif, Vpu, and Nef can promote infection by overcoming the inhibitory effects of the host cell restriction factors APOBEC3G, Tetherin, and SERINC5, respectively. However, how the HIV-1 accessory protein Vpr enhances infection in macrophages but not in CD4+ T cells remains elusive. Here, we report that Vpr counteracts lysosomal-associated transmembrane protein 5 (LAPTM5), a potent inhibitor of HIV-1 particle infectivity, to enhance HIV-1 infection in macrophages. LAPTM5 transports HIV-1 envelope glycoproteins to lysosomes for degradation, thereby inhibiting virion infectivity. Vpr counteracts the restrictive effects of LAPTM5 by triggering its degradation via DCAF1. In the absence of Vpr, the silencing of LAPTM5 precisely phenocopied the effect of Vpr on HIV-1 infection. In contrast, Vpr did not enhance HIV-1 infection in the absence of LAPTM5. Moreover, LAPTM5 was highly expressed in macrophages but not in CD4+ T lymphocytes. Re-expressing LAPTM5 reconstituted the Vpr-dependent promotion of HIV-1 infection in primary CD4+ T cells, as observed in macrophages. Herein, we demonstrate the molecular mechanism used by Vpr to overcome LAPTM5 restriction in macrophages, providing a potential strategy for anti-HIV/AIDS therapeutics.

Date: 2021
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DOI: 10.1038/s41467-021-24087-8

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