The P-selectin ligand PSGL-1 (CD162) is efficiently incorporated by primary HIV-1 isolates and can facilitate trans-infection

Abstract

While P-selectin glycoprotein ligand-1 (PSGL-1/CD162) has been studied extensively for its role in mediating leukocyte rolling through interactions with its receptor, P-selectin, recently, it was identified as a novel HIV-1 host restriction factor. One key mechanism of HIV-1 restriction is the ability of PSGL-1 to be physically incorporated into the external viral envelope, which effectively reduces infectivity by blocking virus attachment through the steric hindrance caused by its large ectodomain. Importantly, a large portion of the literature demonstrating the antiviral activity of PSGL-1 has utilized viruses produced in transfected cells which express high levels of PSGL-1. However, herein we show that virion-incorporated PSGL-1 is far less abundant on the surface of viruses produced via infection of physiologically relevant models (T cell lines and primary cells) compared to transfection (overexpression) models. Unique to this study, we show that PSGL-1 is incorporated in a broad range of HIV-1 and SIV isolates, supporting the physiological relevance of this incorporation. We also report that high levels of virion-incorporated PSGL-1 are detectable in plasma from viremic HIV-1 infected individuals, further corroborating the clinical relevance of PSGL-1 in natural infection. Additionally, we show that PSGL-1 on viruses is functionally active and can bind its cognate receptor, P-selectin, and that virions captured via P-selectin can subsequently be transferred to HIV-permissive bystander cells in a model of trans-infection. Taken together, our data suggest that PSGL-1 may have diverse roles in the physiology of HIV-1 infection, not restricted to the current antiviral paradigm.

Roles of Virion-Incorporated CD162 (PSGL-1), CD43, and CD44 in HIV-1 Infection of T Cells

“…Since PSGL-1 is a ligand of selectin proteins, this interaction might enhance the spread of HIV-1 via trans-infection mediated by P-selectin-expressing cells, such as endothelial cells. Consistent with this possibility, a very recent study showed that P-selectin captures HIV-1 that contains PSGL-1 and that the captured viruses could be efficiently transmitted to target CD4 + T cells [76]. Therefore, HIV-1 containing PSGL-1 might infect CD4 + T cells via trans-infection.…”

“…Therefore, CD44 is likely incorporated into HIV-1 in vivo. In support of this notion, an anti-CD44 antibody and CD44 microbeads interact with viruses derived from the plasma of HIV-1 patients [22,76,97]. Interestingly, when HIV-1 is produced from CD44-expressing cells including PBMCs and hence incorporates CD44, cell-free infection of this HIV-1 is prevented by HA on CD44-expressing target CD4 + T cells at the step of virus attachment [98].…”

“…In addition, CD44 is a ligand of E-selectin, and interactions between CD44 and E-selectin play a role in the recruitment of inflammatory T cells to inflamed tissues [74]. The virion incorporation of CD44 was first identified in the 1990s by independent research groups [19,20] and was validated by subsequent studies [23,75,76]. However, until recently, the role of virion-incorporated CD44 in the spread of HIV-1 remained unclear.…”

“…These effects of PSGL-1, which may represent additional mechanisms for its anti-viral effects, have not been studied using HIV-1 produced from primary CD4 + T cells. Furthermore, a recent study showed that when HIV-1 is produced from PBMCs, gp120 is incorporated into virions despite the presence of PSGL-1 on the surface of virions [76]. Therefore, further studies are needed to determine whether PSGL-1 on the surface of primary CD4 + T cells affects the Env content on the surface of virions and the status of actin in virions.…”