Virion-incorporated PSGL-1 and CD43 inhibit both cell-free infection and transinfection of HIV-1 by preventing virus–cell binding

Abstract

HIV-1 particles incorporate various host transmembrane proteins in addition to viral Env glycoprotein during assembly at the plasma membrane. In polarized T cells, HIV-1 structural protein Gag localizes to the plasma membrane of uropod, a rear-end protrusion. Notably, uropod transmembrane proteins PSGL-1 and CD43 cocluster specifically with Gag assembling at the plasma membrane even in cells that do not form uropods. Recent reports have shown that expression of either PSGL-1 or CD43 in virus-producing cells reduces the infectivity of progeny virions and that HIV-1 infection reduces the cell surface expression of these proteins. However, the mechanisms for both processes remain to be determined. In this study, we found that virion incorporation of PSGL-1 and CD43 closely correlates with diminished virion infectivity. PSGL-1 and CD43 inhibited virus attachment to CD4+cells irrespective of the presence of Env. These proteins also inhibited virion attachment to CD4−lymphoid organ fibroblastic reticular cells that mediate transinfection of CD4+T cells. Consistent with the possibility that highly extended extracellular domains of these proteins physically block virus–cell attachment, the inhibitory effect of PSGL-1 required its full-length ectodomain. HIV-1 encoding Gag mutants that are defective in either coclustering with these host proteins or ESCRT-dependent particle release failed to reduce PSGL-1 on surface of infected cells. This study reveals an anti–HIV-1 mechanism that suppresses virus–cell attachment and a previously unappreciated process of HIV-1-mediated down-regulation of host antiviral proteins, both of which likely require virion incorporation of these proteins.

PSGL-1 inhibits the virion incorporation of SARS-CoV and SARS-CoV-2 spike glycoproteins and impairs virus attachment and infectivity

“…To validate this conclusion, we performed a virion attachment assay, and observed that the lentiviral particles pseudotyped with SARS-CoV or SARS-CoV-2 S protein produced from PSGL-1-expressing cells were impaired in their ability to attach to target cells (Fig. 2), These results demonstrate that the presence of PSGL-1 on virus particles can structurally hinder S protein interaction with the target cells, consistent with our previous studies of PSGL-1 and HIV-1 infection 1,10 .…”

“…PSGL-1 binds to the selectin family of proteins, P-, E-, and L-selectin [2][3][4] , and mediates immune cell tethering and rolling on the surface of endothelium to promote cell migration into inflamed tissues [5][6][7][8] . In the context of viral infection, PSGL-1 has been identified as an IFN-γ-regulated inhibitory factor involved in blocking HIV-1 infectivity 7,9 , and was recently found to possess broad-spectrum antiviral activity 1 , blocking viral infections through steric hindrance of particle attachment to target cells 1,10 .…”

“…Previous studies have demonstrated that PSGL-1 can be incorporated into HIV-1 virions, and its virion incorporation subsequently blocks viral infectivity 1,10 . To investigate the ability of PSGL-1 to restrict coronavirus infection, we first established a lentiviral vector-based coronavirus pseudovirus infection system 15 , in which the S proteins from either SARS-CoV or SARS-CoV-2 were used to pseudotype lentiviral particles ( Fig.…”

PSGL-1 inhibits HIV-1 infection by restricting actin dynamics and sequestering HIV envelope proteins

“…Representative images were shown in j and quantification of images of virions shown in k. Scale bar: 100 nm. review of this study, two papers reported mechanistic studies on PSGL-1's anti-HIV functions 36,37 . These studies proposed a model emphasizing the physical role of virion-incorporated PSGL-1 in occluding virions from attachment to the target cells.…”

“…Potentially anti-HIV drugs could be developed to inhibit Vpu’s antagonism of PSGL-1 and incapacitate the virions. During the preparation and review of this study, two papers reported mechanistic studies on PSGL-1’s anti-HIV functions 36 , 37 . These studies proposed a model emphasizing the physical role of virion-incorporated PSGL-1 in occluding virions from attachment to the target cells.…”