LFA-1 Antagonists as Agents Limiting Human Immunodeficiency Virus Type 1 Infection and Transmission and Potentiating the Effect of the Fusion Inhibitor T-20

Abstract

Adhesion molecules are known to play major roles in the initiation and stabilization of cell-to-cell contacts during the immunological response. Human immunodeficiency virus type 1 (HIV-1) exploits those interactions to facilitate infection and propagation processes. The primary objective of the present study was to investigate the ability of antagonists specific for lymphocyte function-associated antigen 1 (LFA-1) to diminish HIV-1 infection and transmission. We demonstrate here that LFA-1 antagonists can significantly reduce HIV-1 replication in primary human cells and virus propagation by affecting cell-to-cell interactions. Moreover, the inhibition of LFA-1-mediated adhesion events also potentiates the antiviral efficacy of the peptide fusion inhibitor T-20. Altogether, our data suggest that LFA-1 antagonists represent promising antiviral agents. Antiadhesion therapy could be considered a complementary strategy targeting cellular functions essential for HIV-1 spreading and against which the combined therapy currently used displays a limited efficacy.

Broadly Neutralizing Antibody VRC01 Prevents HIV-1 Transmission from Plasmacytoid Dendritic Cells to CD4 T Lymphocytes

“…Second, immunological synapse formation may differ according to the type of cell used. DC-lymphocyte cross talk involves ICAM-1 and LFA-1 adhesion molecules and stabilizes interactions (33,35,43,46,47) that are absent on TZM-bl cell lines (48,49). The strength of the synapse established and the efficiency of HIV-1 transfer may influence the inhibitory activity of HIV-1-specific NAb, making the comparison with different donor/target cell pairs difficult (50).…”

The Role of ERK1/2 Signaling Pathway in Nef Protein Upregulation of the Expression of the Intercellular Adhesion Molecule 1 in Endothelial Cells

“…Antiadhesion therapy could be considered a complementary strategy targeting cellular functions essential for HIV-1 spreading. 21 Our cellular adhesion assay indicated that adhesion of CD4-positive Jurkat cell line to ECV304-Nef cells (endothelial cells) was significantly increased (Figure 4). This result could indicate that Nef contributes to enhancing the virus transmission and spreading through endothelial cells.…”

Early Events of HIV-1 Infection: Can Signaling be the Next Therapeutic Target?

“…Proteomic and lipidomic analyses of purified HIV have confirmed the enrichment of selected lipids and signaling molecules within cell-free virions (Aloia et al 1988(Aloia et al , 1993Brugger et al 2006;Ott 1997Ott , 2002Ott , 2008. While the roles of cholesterol (Campbell et al 2004(Campbell et al , 2002Graham et al 2003;Guyader et al 2002;Liao et al 2003), sphingolipids (Brugger et al 2006), and selected signaling molecules in HIV replication have been confirmed (Giguere et al 2004;Gilbert et al 2007;Ouellet et al 2005;Tardif et al 2009;Tardif and Tremblay 2005), the precise contributions for most of these signaling proteins to HIV infection remains undetermined.…”