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Front. Microbiol. | doi: 10.3389/fmicb.2019.02437

HIV-1 Nef targets HDAC6 to assure viral production and virus infection

Sara Marrero-Hernández1, 2, 3, Daniel Márquez-Arce1, 2, 3,  Romina Cabrera-Rodríguez1, 2, 3, Judith Estévez-Herrera1, 2, 3, Silvia Pérez-Yanes1, 2, 3, Jonathan Barroso-González1, 2, Ricardo Madrid4, José-David Machado1, 2,  Julià Blanco5, 6 and  Agustin Valenzuela-Fernandez1, 2, 3*
  • 1University of La Laguna, Spain
  • 2Faculty of Health Sciences, University of La Laguna, Spain
  • 3Institute of Tropical Diseases and Public Health of the Canary Islands, University of La Laguna, Spain
  • 4Faculty of Biological Science, Complutense University of Madrid, Spain
  • 5IrsiCaixa, Spain
  • 6Universitat de Vic - Universitat Central de Catalunya, Spain

HIV Nef is a central auxiliary protein in HIV infection and pathogenesis. Our results indicate that HDAC6 promotes the aggresome/autophagic degradation of the viral polyprotein Pr55Gag to inhibit HIV-1 production. Nef counteracts this antiviral activity of HDAC6 by inducing its degradation and subsequently stabilizing Pr55Gag and Vif viral proteins. Nef appears to neutralize HDAC6 by an acidic/endosomal-lysosomal processing and not need the downregulation function, since data obtained with the non-associated cell-surface Nef-G2A mutant, the cytoplasmic location of HDAC6, together with studies with chemical inhibitors and other Nef mutants point to this direction. Hence, the polyproline rich region P72xxP75 (69-77 aa) and the di-Leucin motif in the Nef-ExxxLL160-165 sequence of Nef, appear to be responsible for HDAC6 clearance and, therefore, required for this novel Nef proviral function. Nef and Nef-G2A co-immunoprecipitate with HDAC6, whereas the Nef-PPAA mutant showed a reduced interaction with the anti-HIV-1 enzyme. Thus, the P72xxP75 motif appears to be responsible, direct or indirectly, for the interaction of Nef with HDAC6. Remarkably, by neutralizing HDAC6, Nef assures Pr55Gag location and aggregation at plasma membrane, as observed by TIRFM, and promotes viral egress and enhances the infectivity of viral particles. Consequently, our results suggest that HDAC6 acts as anti-HIV-1 restriction factor, limiting viral production and infection by targeting Pr55Gag and Vif. This function is counteracted by functional HIV-1 Nef, in order to assure viral production and infection capacities. The interplay between HIV-1 Nef and cellular HDAC6 may determine viral infection and pathogenesis, representing both molecules key targets to battle HIV.

Keywords: HIV-1, Nef, HDAC6, Pr55gag, Vif, TIRFM, acidic-endocytic/lysosomal degradation, Autophagy, Infection, viral production

Received: 31 Jul 2019; Accepted: 10 Oct 2019.

Copyright: © 2019 Marrero-Hernández, Márquez-Arce, Cabrera-Rodríguez, Estévez-Herrera, Pérez-Yanes, Barroso-González, Madrid, Machado, Blanco and Valenzuela-Fernandez. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Agustin Valenzuela-Fernandez, University of La Laguna, San Cristóbal de La Laguna, 38200, Spain,