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.
Highlights
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
Recent findings derived from replication-competent HIV-1 infection of primary human monocyte-derived macrophages (MDMs) suggest that Vpr plays no role in the first round of infection instead affects the production of the viral envelope glycoprotein Env by overcoming unknown macrophage-specific restriction factors in a DDB1-CUL4-associated factor 1 (DCAF1)-dependent manner[26]
We found that Vpr could induce degradation of the LAPTM5 protein in primary MDMs (Supplementary Fig. 1c), despite the fact that its transcript levels were unaffected (Supplementary Fig. 1d)
Summary
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. Unlike the Gag, Pol, Rev, and Env proteins, essential for HIV-1 replication, Vpr, Vif, Vpu, and Nef are known as accessory proteins because they are not essential for HIV replication in certain cell types[1]. These proteins are necessary for infection in vivo as well as for efficient viral replication in different immune cells in vitro[2]. Ectopic expression of LAPTM5 could significantly inhibit HIV-2 and SIV, but not feline immunodeficiency virus (FIV) or murine leukemia virus (MLV) infectivity, suggesting LAPTM5 to be a potential anti-HIV agent
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