Vpu-Mediated Counteraction of Tetherin Is a Major Determinant of HIV-1 Interferon Resistance
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 restri...
Main Authors: | , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
American Society for Microbiology
2016-08-01
|
Series: | mBio |
Online Access: | http://mbio.asm.org/cgi/content/full/7/4/e00934-16 |
id |
doaj-cf6f8c1e774c49a9a498cc6ae6636df7 |
---|---|
record_format |
Article |
spelling |
doaj-cf6f8c1e774c49a9a498cc6ae6636df72021-07-02T12:58:36ZengAmerican Society for MicrobiologymBio2150-75112016-08-0174e00934-1610.1128/mBio.00934-16Vpu-Mediated Counteraction of Tetherin Is a Major Determinant of HIV-1 Interferon ResistanceDorota KmiecShilpa S. IyerChristina M. SturzelDaniel SauterBeatrice H. HahnFrank KirchhoffHuman 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.http://mbio.asm.org/cgi/content/full/7/4/e00934-16 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Dorota Kmiec Shilpa S. Iyer Christina M. Sturzel Daniel Sauter Beatrice H. Hahn Frank Kirchhoff |
spellingShingle |
Dorota Kmiec Shilpa S. Iyer Christina M. Sturzel Daniel Sauter Beatrice H. Hahn Frank Kirchhoff Vpu-Mediated Counteraction of Tetherin Is a Major Determinant of HIV-1 Interferon Resistance mBio |
author_facet |
Dorota Kmiec Shilpa S. Iyer Christina M. Sturzel 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 |
series |
mBio |
issn |
2150-7511 |
publishDate |
2016-08-01 |
description |
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. |
url |
http://mbio.asm.org/cgi/content/full/7/4/e00934-16 |
work_keys_str_mv |
AT dorotakmiec vpumediatedcounteractionoftetherinisamajordeterminantofhiv1interferonresistance AT shilpasiyer vpumediatedcounteractionoftetherinisamajordeterminantofhiv1interferonresistance AT christinamsturzel vpumediatedcounteractionoftetherinisamajordeterminantofhiv1interferonresistance AT danielsauter vpumediatedcounteractionoftetherinisamajordeterminantofhiv1interferonresistance AT beatricehhahn vpumediatedcounteractionoftetherinisamajordeterminantofhiv1interferonresistance AT frankkirchhoff vpumediatedcounteractionoftetherinisamajordeterminantofhiv1interferonresistance |
_version_ |
1721329598011015168 |