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

ABSTRACT 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. Among these, only Vpu proteins of pandemic HIV-1 group M strains evolved potent activity against t...

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Autores principales:	Dorota Kmiec, Shilpa S. Iyer, Christina M. Stürzel, Daniel Sauter, Beatrice H. Hahn, Frank Kirchhoff
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/6dae67beccce4aa2b37a5b00912b36fb
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spelling	oai:doaj.org-article:6dae67beccce4aa2b37a5b00912b36fb2021-11-15T15:50:18ZVpu-Mediated Counteraction of Tetherin Is a Major Determinant of HIV-1 Interferon Resistance10.1128/mBio.00934-162150-7511https://doaj.org/article/6dae67beccce4aa2b37a5b00912b36fb2016-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00934-16https://doaj.org/toc/2150-7511ABSTRACT 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. 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. IMPORTANCE Understanding which human-specific adaptations allowed HIV-1 to cause the AIDS pandemic is of great importance. One feature that distinguishes pandemic HIV-1 group M strains from nonpandemic or rare group O, N, and P viruses is the acquisition of mutations in the accessory Vpu protein that confer potent activity against human tetherin. Adaptation was required because human tetherin has a deletion that renders it resistant to the Nef protein used by the SIV precursor of HIV-1 to antagonize this antiviral factor. It has been suggested that these adaptations in Vpu were critical for the effective spread of HIV-1 M strains, but direct evidence has been lacking. Here, we show that these changes in Vpu significantly enhance virus replication and release in human CD4+ T cells, particularly in the presence of IFN, thus supporting an important role in the spread of pandemic HIV-1.Dorota KmiecShilpa S. IyerChristina M. StürzelDaniel SauterBeatrice H. HahnFrank KirchhoffAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 4 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Dorota Kmiec Shilpa S. Iyer Christina M. Stürzel Daniel Sauter Beatrice H. Hahn Frank Kirchhoff Vpu-Mediated Counteraction of Tetherin Is a Major Determinant of HIV-1 Interferon Resistance
description	ABSTRACT 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. 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. IMPORTANCE Understanding which human-specific adaptations allowed HIV-1 to cause the AIDS pandemic is of great importance. One feature that distinguishes pandemic HIV-1 group M strains from nonpandemic or rare group O, N, and P viruses is the acquisition of mutations in the accessory Vpu protein that confer potent activity against human tetherin. Adaptation was required because human tetherin has a deletion that renders it resistant to the Nef protein used by the SIV precursor of HIV-1 to antagonize this antiviral factor. It has been suggested that these adaptations in Vpu were critical for the effective spread of HIV-1 M strains, but direct evidence has been lacking. Here, we show that these changes in Vpu significantly enhance virus replication and release in human CD4+ T cells, particularly in the presence of IFN, thus supporting an important role in the spread of pandemic HIV-1.
format	article
author	Dorota Kmiec Shilpa S. Iyer Christina M. Stürzel Daniel Sauter Beatrice H. Hahn Frank Kirchhoff
author_facet	Dorota Kmiec Shilpa S. Iyer Christina M. Stürzel Daniel Sauter Beatrice H. Hahn Frank Kirchhoff
author_sort	Dorota Kmiec
title	Vpu-Mediated Counteraction of Tetherin Is a Major Determinant of HIV-1 Interferon Resistance
title_short	Vpu-Mediated Counteraction of Tetherin Is a Major Determinant of HIV-1 Interferon Resistance
title_full	Vpu-Mediated Counteraction of Tetherin Is a Major Determinant of HIV-1 Interferon Resistance
title_fullStr	Vpu-Mediated Counteraction of Tetherin Is a Major Determinant of HIV-1 Interferon Resistance
title_full_unstemmed	Vpu-Mediated Counteraction of Tetherin Is a Major Determinant of HIV-1 Interferon Resistance
title_sort	vpu-mediated counteraction of tetherin is a major determinant of hiv-1 interferon resistance
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/6dae67beccce4aa2b37a5b00912b36fb
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Vpu-Mediated Counteraction of Tetherin Is a Major Determinant of HIV-1 Interferon Resistance

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