Background: As the initial barrier to viral entry, the plasma membrane along with membrane trafficking machinery and cytoskeleton are of fundamental importance in the viral cycle. However little is known about the contribution of plasma membrane dynamics during early HIV-1 infection. ARF6 regulates cellular invasion via several microorganisms by coordi- nating membrane trafficking. Our aim was to study the function of ARF6-mediated membrane dynamics on HIV-1 entry and infection of T lymphocytes. Observations: We observed that an alteration of the ARF6-GTP/ GDP cycle, by expression of GDP-bound or GTP-bound inactive mutants or by specific ARF6 silencing, significantly inhibited HIV-1 infection of T lymphocytes and permissive cells, regard- less of viral tropism. Furthermore, cell-to-cell HIV-1 transmis- sion of primary human CD4+ T lymphocytes was inhibited by ARF6 knock-down. ARF6 silencing or its mutants did not affect the infection of VSV-G pseudotyped viruses or ligand-induced CXCR4 or CCR5 endocytosis, both clathrin-dependent processes. Conclusions: Our results show that ARF6 silencing inhibits HIV-1 infection, regardless of viral tropism and without affecting the membrane distribution of the HIV-1 co-receptors CXCR4/ CCR5. We therefore propose that efficient early HIV-1 infection requires an ARF6-coordinated plasma membrane dynamics.
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