Article | Published:

HIV-1 Nef promotes infection by excluding SERINC5 from virion incorporation

Nature volume 526, pages 212217 (08 October 2015) | Download Citation

Abstract

HIV-1 Nef, a protein important for the development of AIDS, has well-characterized effects on host membrane trafficking and receptor downregulation. By an unidentified mechanism, Nef increases the intrinsic infectivity of HIV-1 virions in a host-cell-dependent manner. Here we identify the host transmembrane protein SERINC5, and to a lesser extent SERINC3, as a potent inhibitor of HIV-1 particle infectivity that is counteracted by Nef. SERINC5 localizes to the plasma membrane, where it is efficiently incorporated into budding HIV-1 virions and impairs subsequent virion penetration of susceptible target cells. Nef redirects SERINC5 to a Rab7-positive endosomal compartment and thereby excludes it from HIV-1 particles. The ability to counteract SERINC5 was conserved in Nef encoded by diverse primate immunodeficiency viruses, as well as in the structurally unrelated glycosylated Gag from murine leukaemia virus. These examples of functional conservation and convergent evolution emphasize the fundamental importance of SERINC5 as a potent anti-retroviral factor.

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Accessions

Primary accessions

Sequence Read Archive

Referenced accessions

GenBank/EMBL/DDBJ

Data deposits

RNA-seq fatsq data have been deposited in NCBI Sequence Read Archive (SRA) under accession code SRP062444.

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Acknowledgements

We thank the Centre for AIDS Reagents, NIBSC, and NIH AIDS Research and Reference Reagent Program, Division of AIDS, for cell lines, plasmids and antibodies. We thank V. Adami and the CIBIO high-throughput screening and the Advanced Imaging facilities staff for technical assistance, G. De Silvestro, G. Mattiuzzo, C. Reinhard and L. Conti for reagents, G. Melikian, S. Basmaciogullari, P. Cherepanov, O. Fackler, N. Segata, F. Demichelis, A. Marcello, T. Fedrizzi and A. Helander for critical discussions. This work was supported by the Biotechnology Program of University of Trento, FP7 Marie Curie Career Integration grant number 322130 and Caritro ‘Ricerca Biomedica’ grant number 2013.0248 to M.P., National Institute of Health grant DP1DA034990 to J.L. and European Research Council grant 249968 to S.E.A.

Author information

Author notes

    • Annachiara Rosa
    • , Ajit Chande
    •  & Serena Ziglio

    These authors contributed equally to this work.

Affiliations

  1. University of Trento, Centre for Integrative Biology, 38123 Trento, Italy

    • Annachiara Rosa
    • , Ajit Chande
    • , Serena Ziglio
    •  & Massimo Pizzato
  2. University of Trento, Laboratory of Biomolecular Sequence and Structure Analysis for Health, NGS facility, 38123 Trento, Italy

    • Veronica De Sanctis
    •  & Roberto Bertorelli
  3. University of Massachusetts Medical School, Program in Molecular Medicine, Worcester, Massachusetts 01605, USA

    • Shih Lin Goh
    • , Sean M. McCauley
    • , Anetta Nowosielska
    •  & Jeremy Luban
  4. University of Geneva, Department of Genetic Medicine and Development, Geneva 1211, Switzerland

    • Stylianos E. Antonarakis
    •  & Federico Andrea Santoni
  5. iGE3 Institute of Genetics and Genomics of Geneva, Geneva 1211, Switzerland

    • Stylianos E. Antonarakis

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Contributions

A.R., A.C., S.Z., V.D.S., R.B., S.E.A., J.L., F.A.S. and M.P. designed the experiments. A.R., S.Z., A.C., V.D.S., R.B., S.L.G., S.M.M., A.N., F.A.S. and M.P. performed the experiments. All authors contributed to the assembly and writing of the manuscript. A.R., A.C. and S.Z. contributed equally to the study.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Massimo Pizzato.

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DOI

https://doi.org/10.1038/nature15399

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