HIV-1 Tat inhibits phagocytosis by preventing the recruitment of Cdc42 to the phagocytic cup

Solène Debaisieux, Simon Lachambre, Antoine Gross, Clément Mettling, Sébastien Besteiro, Hocine Yezid, Daniel Henaff, Christophe Chopard, Jean-Michel Mesnard and Bruno Beaumelle ()
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Solène Debaisieux: CPBS, UMR 5236 CNRS-Université de Montpellier
Simon Lachambre: CPBS, UMR 5236 CNRS-Université de Montpellier
Antoine Gross: CPBS, UMR 5236 CNRS-Université de Montpellier
Clément Mettling: IGH, UPR 1142 CNRS
Sébastien Besteiro: DIMNP, UMR 5235 CNRS, Université de Montpellier
Hocine Yezid: CPBS, UMR 5236 CNRS-Université de Montpellier
Daniel Henaff: CPBS, UMR 5236 CNRS-Université de Montpellier
Christophe Chopard: CPBS, UMR 5236 CNRS-Université de Montpellier
Jean-Michel Mesnard: CPBS, UMR 5236 CNRS-Université de Montpellier
Bruno Beaumelle: CPBS, UMR 5236 CNRS-Université de Montpellier

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: Abstract Most macrophages remain uninfected in HIV-1-infected patients. Nevertheless, the phagocytic capacity of phagocytes from these patients is impaired, favouring the multiplication of opportunistic pathogens. The basis for this phagocytic defect is not known. HIV-1 Tat protein is efficiently secreted by infected cells. Secreted Tat can enter uninfected cells and reach their cytosol. Here we found that extracellular Tat, at the subnanomolar concentration present in the sera of HIV-1-infected patients, inhibits the phagocytosis of Mycobacterium avium or opsonized Toxoplasma gondii by human primary macrophages. This inhibition results from a defect in mannose- and Fcγ-receptor-mediated phagocytosis, respectively. Inhibition relies on the interaction of Tat with phosphatidylinositol (4,5)bisphosphate that interferes with the recruitment of Cdc42 to the phagocytic cup, thereby preventing Cdc42 activation and pseudopod elongation. Tat also inhibits FcγR-mediated phagocytosis in neutrophils and monocytes. This study provides a molecular basis for the phagocytic defects observed in uninfected phagocytes following HIV-1 infection.

Date: 2015
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DOI: 10.1038/ncomms7211

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