Abstract
PSGL-1 has recently been identified as an HIV restriction factor that inhibits HIV DNA synthesis and more potently, virion infectivity. But the underlying mechanisms of these inhibitions are unknown. Here we show that PSGL-1 directly binds to cellular actin filaments (F-actin) to restrict actin dynamics, which leads to inhibition of HIV DNA synthesis. PSGL-1 is incorporated into nascent virions and restricts actin dynamics in the virions, which partially accounts for the inhibition of virion infectivity. More potently, PSGL-1 inhibits incorporation of Env proteins into nascent virions, causing a loss of envelope spikes on the virions as shown by Cryo-electron microscopy and super-resolution imaging. This loss is associated with a profound defect in viral entry. Mechanistically, PSGL-1 binds gp41 and sequesters gp41 at the plasma membrane, explaining the inhibition of Env incorporation in nascent virions. PSGL-1’s dual anti-HIV mechanisms represent novel strategies of human cells to defend against HIV infection.
Highlights
Introduction HIV1 infection redirects the cellular machinery towards mass production of new infectious virions, which renders the virus vulnerable to host defense strategies to undermine this production line[1,2,3,4,5,6]
We confirmed that P-selectin glycoprotein ligand 1 (PSGL-1) can be co-immunoprecipitated with actin and this co-immunoprecipitation is abolished when the cytoplasmic domain (CD) is deleted in Supplementary Fig. S1a
For the early inhibition of HIV DNA synthesis, PSGL-1 acts by binding with F-actin and restricting cellular actin dynamics (Fig. 5g)
Summary
Introduction HIV1 infection redirects the cellular machinery towards mass production of new infectious virions, which renders the virus vulnerable to host defense strategies to undermine this production line[1,2,3,4,5,6]. HIV-1 restriction factors, including TRIM5α, APOBEC3, tetherin, SAMHD1, and SERINC3/SERINC5, are a small number of well-studied ISGs that block HIV-1 replication cycles at. Given this reoccurring HIV-1-induced degradation of restriction factors, we conducted a genome-wide proteomic profiling of HIV-1 infection in primary human CD4+ T cells and identified a new HIV-1 restriction factor, P-selectin glycoprotein ligand 1 (PSGL-1)[10]. PSGL-1 is induced by interferon γ (IFN-γ) and mediates the bulk of IFN-γ’s anti-HIV-1 activity in primary CD4+ T cells[10] To overcome this restriction, HIV-1 Vpu binds to PSGL-1 and recruits it to the E3 ligase, SCF β-TrCP2 for ubiquitination and subsequent proteasomal degradation[10]. IFN-γ has largely been considered as an immunomodulatory cytokine and its direct anti-HIV activity is starting to be
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