Differential Vpu-Mediated CD4 and Tetherin Downregulation Functions among Major HIV-1 Group M Subtypes

Author:

Umviligihozo Gisele1,Cobarrubias Kyle D.1,Chandrarathna Sandali1,Jin Steven W.1,Reddy Nicole23,Byakwaga Helen45,Muzoora Conrad4,Bwana Mwebesa B.4,Lee Guinevere Q.6,Hunt Peter W.5,Martin Jeff N.5,Brumme Chanson J.67,Bangsberg David R.8,Karita Etienne9,Allen Susan91011,Hunter Eric912,Ndung’u Thumbi231314,Brumme Zabrina L.16ORCID,Brockman Mark A.16ORCID

Affiliation:

1. Faculty of Health Sciences, Simon Fraser University, Vancouver, British Columbia, Canada

2. University of KwaZulu-Natal, Durban, South Africa

3. Africa Health Research Institute, Durban, South Africa

4. Mbarara University of Science and Technology, Mbarara, Uganda

5. University of California, San Francisco, California, USA

6. British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada

7. University of British Columbia, Vancouver, British Columbia, Canada

8. Oregon Health and Science University-Portland State University School of Public Health, Portland, Oregon, USA

9. Rwanda Zambia HIV Research Group-Projet San Francisco, Kigali, Rwanda

10. Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA

11. Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA

12. Emory Vaccine Center at Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA

13. Max Planck Institute for Infection Biology, Berlin, Germany

14. Division of Infection and Immunity, University College London, London, United Kingdom

Abstract

The HIV-1 accessory protein Vpu enhances viral spread by downregulating CD4 and BST-2/tetherin on the surface of infected cells. Natural variability in these Vpu functions may contribute to HIV-1 pathogenesis, but this has not been investigated among the diverse viral subtypes that contribute to the HIV-1 pandemic. In this study, we found that Vpu function differs significantly among HIV-1 subtypes A, B, C, and D. On average, subtype C clones displayed the lowest ability to downregulate both CD4 and tetherin, while subtype B and D clones were more functional. We also identified Vpu polymorphisms that associate with functional differences among HIV-1 isolates and subtypes. Our study suggests that genetic diversity in Vpu may play an important role in the differential pathogenesis and/or spread of HIV-1.

Funder

HHS | National Institutes of Health

Michael Smith Foundation for Health Research

Canada Research Chairs

Gouvernement du Canada | Canadian Institutes of Health Research

African Academy of Sciences

Wellcome Trust

Publisher

American Society for Microbiology

Subject

Virology,Insect Science,Immunology,Microbiology

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