Cocaine Enhances DC to T-cell HIV-1 Transmission by Activating DC-SIGN/LARG/LSP1 Complex and Facilitating Infectious Synapse Formation

Abstract

DC-SIGN is a dendritic cell surface structure which participates in binding and transmission of HIV-1. Here, for the first time we demonstrate that cocaine induces over expression of DC-SIGN and significantly enhances virus transfer from DCs to T-cells by increasing the binding and internalization of HIV-1 in DCs. We found that cocaine activates a DC-SIGN mediated ‘signalosome’ complex by enhancing its association with LARG and LSP1. Further, LARG was observed to participate in DC-SIGN mediated internalization of HIV-1 in DCs. Intracellular trafficking studies of HIV-1 in cocaine treated DCs revealed increased co-localization of HIV-1 with endosomal or multi vesicular body (MVB) markers such as CD81 and VPS4 and decreased co-localization with the phagolysomal marker LAMP1; this signified altered intracellular trafficking and decreased degradation of HIV-1 in cocaine treated DCs. Furthermore, we found that cocaine induced activation of LARG which in turn activated Rho A and the focal adhesion molecules FAK, Pyk2 and paxillin. This signaling cascade enhanced the formation of an infectious synapse between DCs and T-cells. Our study provides insight into the molecular mechanisms of cocaine’s contribution to key components in HIV pathogenesis and highlights novel targets for interrupting the virus life cycle in substance using hosts.

LSP1-myosin1e bi-molecular complex regulates focal adhesion dynamics and cell migration

“…activation (Anand et al, 2009;Prasad et al, 2017;Prasad et al, 2012). This study, thus, support our findings highlighting the key role of LSP1 in the regulation of focal adhesion dynamics and cell migration.…”

“…In this context, it has been shown that the human immunodeficiency virus can induce migration of dendritic cells (Anand et al, 2009). These viruses control dendritic cell migration by the binding of their envelope protein gp120 to DC-SIGN on dendritic cells (Prasad et al, 2017;Prasad et al, 2012). Remarkably, gp120-DC-SIGN interaction triggers a signalling cascade that involves LSP1 and leads to Rho GTPase (a regulator of focal adhesion dynamics)…”

An atypical subacute presentation of posterior reversible encephalopathy syndrome

“…Cocaine has been shown to synergistically enhance the pathologic processes induced by HIV infection [23–25]. Cocaine is also known to induce oxidative stress, tight junction disruption, endothelial cell inflammation dysfunction, and loss of BBB integrity [26–28].…”

Dendritic Cells, the Double Agent in the War Against HIV-1

“…Besides being essential for the formation of the synapse, DC-SIGN binding to HIV-1 particle in the first place also sets a signaling cascade that favors the trans-infection pathway over productive infection or viral degradation. DC-SIGN is known to associate with LARG, whose activation promotes activation of RhoA and the focal adhesion molecules FAK, Pyk2, and paxillin, all of them structural components of the infectious synapse (199).…”