Vpu-Mediated Counteraction of Tetherin Is a Major Determinant of HIV-1 Interferon Resistance

Dorota Kmiec,Beatrice H Hahn,Daniel Sauter,Frank Kirchhoff,Christina M Stürzel,Shilpa S Iyer,Stephen P Goff

doi:10.1128/mbio.00934-16

Abstract

ABSTRACTHuman immunodeficiency virus type 1 (HIV-1) groups M, N, O, and P are the result of independent zoonotic transmissions of simian immunodeficiency viruses (SIVs) infecting great apes in Africa. Among these, only Vpu proteins of pandemic HIV-1 group M strains evolved potent activity against the restriction factor tetherin, which inhibits virus release from infected cells. Thus, effective Vpu-mediated tetherin antagonism may have been a prerequisite for the global spread of HIV-1. To determine whether this particular function enhances primary HIV-1 replication and interferon resistance, we introduced mutations into the vpu genes of HIV-1 group M and N strains to specifically disrupt their ability to antagonize tetherin, but not other Vpu functions, such as degradation of CD4, down-modulation of CD1d and NTB-A, and suppression of NF-κB activity. Lack of particular human-specific adaptations reduced the ability of HIV-1 group M Vpu proteins to enhance virus production and release from primary CD4+ T cells at high levels of type I interferon (IFN) from about 5-fold to 2-fold. Interestingly, transmitted founder HIV-1 strains exhibited higher virion release capacity than chronic control HIV-1 strains irrespective of Vpu function, and group M viruses produced higher levels of cell-free virions than an N group HIV-1 strain. Thus, efficient virus release from infected cells seems to play an important role in the spread of HIV-1 in the human population and requires a fully functional Vpu protein that counteracts human tetherin.

Highlights

Human immunodeficiency virus type 1 (HIV-1) groups M, N, O, and P are the result of independent zoonotic transmissions of simian immunodeficiency viruses (SIVs) infecting great apes in Africa
To examine the effects of Vpumediated tetherin antagonism on HIV-1 replication and IFN sensitivity in human CD4ϩ T cells, we generated a panel of infectious molecular clones (IMCs) that lacked this specific Vpu proteins (Vpus) function
It has been suggested that the acquisition of Vpu-mediated tetherin antagonism promoted efficient spread of HIV/AIDS [10, 11]

Summary

Introduction

Human immunodeficiency virus type 1 (HIV-1) groups M, N, O, and P are the result of independent zoonotic transmissions of simian immunodeficiency viruses (SIVs) infecting great apes in Africa. Only Vpu proteins of pandemic HIV-1 group M strains evolved potent activity against the restriction factor tetherin, which inhibits virus release from infected cells. Pandemic group M and (to a much lesser extent) rare group N strains acquired Vpu-mediated antitetherin activity [5, 12], while HIV-1 group O strains evolved the ability to counteract human tetherin by adapting their Nef protein to target a region adjacent to the deletion [13]. We introduced mutations in the TMDs of the Vpu proteins of six group M infectious molecular clones (IMCs) that abrogated their ability to antagonize human tetherin We show that these changes significantly decrease HIV-1 replication and increase IFN sensitivity in primary human CD4ϩ T cells. Human-specific adaptation of SIVcpz Vpu was likely required to gain maximal replication fitness of group M viruses in the new host and facilitate the successful colonization of humans

Methods

Results

Conclusion