Link between Primate Lentiviral Coreceptor Usage and Nef Function
Simian immunodeficiency virus (SIVsmm) infection of sooty mangabeys (Cercocebus atys) is characterized by stable CD4+ T cell counts despite high plasma levels of CCR5-tropic viruses. However, in rare instances, SIVsmm acquires CXCR4 coreceptor tropism and causes severe CD4+ T cell depletion, albeit...
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doaj-72f6647727c64faeb397698cd53b9aa22020-11-24T22:01:13ZengElsevierCell Reports2211-12472013-11-0154997100910.1016/j.celrep.2013.10.028Link between Primate Lentiviral Coreceptor Usage and Nef FunctionJan Schmökel0Hui Li1Asma Shabir2Hangxing Yu3Matthias Geyer4Guido Silvestri5Donald L. Sodora6Beatrice H. Hahn7Frank Kirchhoff8Institute of Molecular Virology, University of Ulm, 89069 Ulm, GermanyDepartment of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAInstitute of Molecular Virology, University of Ulm, 89069 Ulm, GermanyInstitute of Molecular Virology, University of Ulm, 89069 Ulm, GermanyCenter of Advanced European Studies and Research (CAESAR), Physical Biochemistry Group, 53175 Bonn, GermanyYerkes Regional Primate Research Center, Emory University, Atlanta, GA 30322, USASeattle Biomedical Research Institute, Seattle, WA 98109, USADepartment of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAInstitute of Molecular Virology, University of Ulm, 89069 Ulm, Germany Simian immunodeficiency virus (SIVsmm) infection of sooty mangabeys (Cercocebus atys) is characterized by stable CD4+ T cell counts despite high plasma levels of CCR5-tropic viruses. However, in rare instances, SIVsmm acquires CXCR4 coreceptor tropism and causes severe CD4+ T cell depletion, albeit without clinical signs of immunodeficiency. Here, we show that CXCR4-tropic SIVsmm strains lost their ability to downmodulate TCR-CD3 by evolving unusual Nef mutations that initially reduced (I132V) and subsequently disrupted (I123L and L146F) interaction with the CD3 ζ chain. This coevolution of Env and Nef function suggests that CD3 downmodulation is advantageous for viral replication in activated CCR5+ memory T cells, but not in resting naive CXCR4+ T cells that have not yet undergone TCR-CD3-mediated stimulation. This may explain why HIV-1, which generally lacks the CD3 downmodulation function, commonly switches to CXCR4 usage, whereas this is extremely rare for SIV strains that have retained this Nef activity. http://www.sciencedirect.com/science/article/pii/S2211124713006128 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jan Schmökel Hui Li Asma Shabir Hangxing Yu Matthias Geyer Guido Silvestri Donald L. Sodora Beatrice H. Hahn Frank Kirchhoff |
spellingShingle |
Jan Schmökel Hui Li Asma Shabir Hangxing Yu Matthias Geyer Guido Silvestri Donald L. Sodora Beatrice H. Hahn Frank Kirchhoff Link between Primate Lentiviral Coreceptor Usage and Nef Function Cell Reports |
author_facet |
Jan Schmökel Hui Li Asma Shabir Hangxing Yu Matthias Geyer Guido Silvestri Donald L. Sodora Beatrice H. Hahn Frank Kirchhoff |
author_sort |
Jan Schmökel |
title |
Link between Primate Lentiviral Coreceptor Usage and Nef Function |
title_short |
Link between Primate Lentiviral Coreceptor Usage and Nef Function |
title_full |
Link between Primate Lentiviral Coreceptor Usage and Nef Function |
title_fullStr |
Link between Primate Lentiviral Coreceptor Usage and Nef Function |
title_full_unstemmed |
Link between Primate Lentiviral Coreceptor Usage and Nef Function |
title_sort |
link between primate lentiviral coreceptor usage and nef function |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2013-11-01 |
description |
Simian immunodeficiency virus (SIVsmm) infection of sooty mangabeys (Cercocebus atys) is characterized by stable CD4+ T cell counts despite high plasma levels of CCR5-tropic viruses. However, in rare instances, SIVsmm acquires CXCR4 coreceptor tropism and causes severe CD4+ T cell depletion, albeit without clinical signs of immunodeficiency. Here, we show that CXCR4-tropic SIVsmm strains lost their ability to downmodulate TCR-CD3 by evolving unusual Nef mutations that initially reduced (I132V) and subsequently disrupted (I123L and L146F) interaction with the CD3 ζ chain. This coevolution of Env and Nef function suggests that CD3 downmodulation is advantageous for viral replication in activated CCR5+ memory T cells, but not in resting naive CXCR4+ T cells that have not yet undergone TCR-CD3-mediated stimulation. This may explain why HIV-1, which generally lacks the CD3 downmodulation function, commonly switches to CXCR4 usage, whereas this is extremely rare for SIV strains that have retained this Nef activity.
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url |
http://www.sciencedirect.com/science/article/pii/S2211124713006128 |
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