Abstract
Cell-mediated transmission and dissemination of sexually-acquired human immunodeficiency virus 1 (HIV-1) in the host involves the migration of immature dendritic cells (iDCs). iDCs migrate in response to the HIV-1 envelope protein, gp120, and inhibiting such migration may limit the mucosal transmission of HIV-1. In this study, we elucidated the mechanism of HIV-1-gp120-induced transendothelial migration of iDCs. We found that gp120 enhanced the binding of Wiskott-Aldrich Syndrome protein (WASp) and the Actin-Related Protein 2/3 (Arp2/3) complex with β-actin, an interaction essential for the proper formation of podosomes, specialized adhesion structures required for the migration of iDCs through different tissues. We further identified Leukocyte-Specific Protein 1 (LSP1) as a novel component of the WASp-Arp2/3-β-actin complex. Pretreating iDCs with an active fragment of the secretory glycoprotein Slit2 (Slit2N) inhibited HIV-1-gp120-mediated migration and podosome formation, by inducing the cognate receptor Roundabout 1 (Robo1) to bind to and sequester WASp and LSP1 from β-actin. Slit2N treatment also inhibited Src signaling and the activation of several downstream molecules, including Rac1, Pyk2, paxillin, and CDC42, a major regulator of podosome formation. Taken together, our results support a novel mechanism by which Slit2/Robo1 may inhibit the HIV-1-gp120-induced migration of iDCs, thereby restricting dissemination of HIV-1 from mucosal surfaces in the host.
Highlights
After sexual contact with human immunodeficiency virus 1 (HIV-1), immature DCs capture the virus in submucosal tissue and migrate to lymphoid tissues where they infect CD4+ T cells
Since proper podosome function appears to be necessary for immature DCs (iDCs) migration, we examined the effects of M-gp120 and Slit2 on both podosome formation and localization in iDCs, the complexing of key core podosome-associated proteins, Wiskott-Aldrich Syndrome protein (WASp), Actin-Related Protein 2/3 (Arp2/3) and b-actin
M-gp120 can induce the migration of iDCs in vitro [34], and Slit2 has been shown to inhibit the migration of various immune cells, including dendritic cells [19,20,21,22]
Summary
After sexual contact with HIV-1, immature DCs (iDCs) capture the virus in submucosal tissue and migrate to lymphoid tissues where they infect CD4+ T cells. These initial stages of HIV-1 infection result in rapid dissemination of the pathogen throughout the host [1,2,3,4,5]. Nonmigrating cells can generate lamellipodia; in contrast to migrating DCs, they produce multiple lamellipodia that protrude at various points around the cell This prevents the cells from adopting a polar orientation, and results in no net motility [9]
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