Prestimulation of CD2 confers resistance to HIV-1 latent infection in blood resting CD4 T cells

Sijia He,Jia Guo,Yajing Fu,Mark Spear,Chaolong Qin,Shuai Fu,Zongqiang Cui,Wenwen Jin,Xuehua Xu,Wanjun Chen,Hong Shang,Yuntao Wu

doi:10.1016/j.isci.2021.103305

Abstract

SummaryHIV-1 infects blood CD4 T cells through the use of CD4 and CXCR4 or CCR5 receptors, which can be targeted through blocking viral binding to CD4/CXCR4/CCR5 or virus-cell fusion. Here we describe a novel mechanism by which HIV-1 nuclear entry can also be blocked through targeting a non-entry receptor, CD2. Cluster of differentiation 2 (CD2) is an adhesion molecule highly expressed on human blood CD4, particularly, memory CD4 T cells. We found that CD2 ligation with its cell-free ligand LFA-3 or anti-CD2 antibodies rendered blood resting CD4 T cells highly resistant to HIV-1 infection. We further demonstrate that mechanistically, CD2 binding initiates competitive signaling leading to cofilin activation and localized actin polymerization around CD2, which spatially inhibits HIV-1-initiated local actin polymerization needed for viral nuclear migration. Our study identifies CD2 as a novel target to block HIV-1 infection of blood resting T cells.

Highlights

Prestimulation of Cluster of differentiation 2 (CD2) inhibits HIV-1 latent infection of resting CD4 T cells To determine the effects of CD2 signaling on HIV infection of blood CD4 T cells, we first quantified CD2 expression on human blood resting CD4 T cells and found that both memory (CD45RO+) and naıve (CD45ROÀ) T cells expressed CD2, with memory T cells naturally expressing higher levels of surface CD2 (Iglesias-Ussel et al, 2013) (Figure S1)
When resting T cells were prestimulated with the antiCD2 antibody, we observed 90%–99% inhibition of HIV-1 latent infection of resting CD4 T cells (Figures 1A–1F); this CD2-mediated inhibition has been tested in a total of eight donors, and we observed strong inhibition in all donors tested
Similar to the enhancement of X4 virus infection by prestimulation of CXCR4 (Figure 1C) (Yoder et al, 2008), CXCR4 prestimulation enhanced the latent infection of memory CD4 T cells by the R5 virus (Figure 1F), which is in great contrast to the potent inhibition of HIV latent infection of memory T cells by CD2 prestimulation

Summary

Introduction

HIV infects and enters blood CD4 T cells through the use of CD4 (Dalgleish et al, 1984; Klatzmann et al, 1984) and the chemokine coreceptor, CXCR4 (Feng et al, 1996) or CCR5 (Alkhatib et al, 1996; Choe et al, 1996; Cocchi et al, 1995; Combadiere et al, 1996; Deng et al, 1996; Doranz et al, 1996; Dragic et al, 1996). It has been suggested that the static cortical actin in blood resting T cells represents a barrier for viral entry and nuclear migration (Wang et al, 2012; Yoder et al, 2008) To overcome this restriction, HIV-1 relies on gp120 binding to CXCR4 or CCR5 to activate actin modulators such as cofilin to promote actin dynamics necessary for viral entry and nuclear migration (He et al, 2019; Spear et al, 2014; Vorster et al, 2011; Yoder et al, 2008). Blocking HIV-mediated G protein signaling and actin dynamics, using inhibitors such as pertussis toxin or the LIMK and Arp2/3 inhibitors, has been shown to block HIV infection of blood resting T cells (Spear et al, 2014; Vorster et al, 2011; Yi et al, 2017; Yoder et al, 2008)

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