Convergent Evolution of HLA-C Downmodulation in HIV-1 and HIV-2

ABSTRACT HLA-C-mediated antigen presentation induces the killing of human immunodeficiency virus (HIV)-infected CD4+ T cells by cytotoxic T lymphocytes (CTLs). To evade killing, many HIV-1 group M strains decrease HLA-C surface levels using their accessory protein Vpu. However, some HIV-1 group M is...

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Autores principales:	Kristina Hopfensperger, Jonathan Richard, Christina M. Stürzel, Frederic Bibollet-Ruche, Richard Apps, Marie Leoz, Jean-Christophe Plantier, Beatrice H. Hahn, Andrés Finzi, Frank Kirchhoff, Daniel Sauter
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	HIV-1 HIV-2 SIV HLA-C Vpu Vif Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/839388e6abb74760963d4aefd5626c6e
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spelling	oai:doaj.org-article:839388e6abb74760963d4aefd5626c6e2021-11-15T15:56:44ZConvergent Evolution of HLA-C Downmodulation in HIV-1 and HIV-210.1128/mBio.00782-202150-7511https://doaj.org/article/839388e6abb74760963d4aefd5626c6e2020-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00782-20https://doaj.org/toc/2150-7511ABSTRACT HLA-C-mediated antigen presentation induces the killing of human immunodeficiency virus (HIV)-infected CD4+ T cells by cytotoxic T lymphocytes (CTLs). To evade killing, many HIV-1 group M strains decrease HLA-C surface levels using their accessory protein Vpu. However, some HIV-1 group M isolates lack this activity, possibly to prevent the activation of natural killer (NK) cells. Analyzing diverse primate lentiviruses, we found that Vpu-mediated HLA-C downregulation is not limited to pandemic group M but is also found in HIV-1 groups O and P as well as several simian immunodeficiency viruses (SIVs). We show that Vpu targets HLA-C primarily at the protein level, independently of its ability to suppress NF-κB-driven gene expression, and that in some viral lineages, HLA-C downregulation may come at the cost of efficient counteraction of the restriction factor tetherin. Remarkably, HIV-2, which does not carry a vpu gene, uses its accessory protein Vif to decrease HLA-C surface expression. This Vif activity requires intact binding sites for the Cullin5/Elongin ubiquitin ligase complex but is separable from its ability to counteract APOBEC3G. Similar to HIV-1 Vpu, the degree of HIV-2 Vif-mediated HLA-C downregulation varies considerably among different virus isolates. In agreement with opposing selection pressures in vivo, we show that the reduction of HLA-C surface levels by HIV-2 Vif is accompanied by increased NK cell-mediated killing. In summary, our results highlight the complex role of HLA-C in lentiviral infections and demonstrate that HIV-1 and HIV-2 have evolved at least two independent mechanisms to decrease HLA-C levels on infected cells. IMPORTANCE Genome-wide association studies suggest that HLA-C expression is a major determinant of viral load set points and CD4+ T cell counts in HIV-infected individuals. On the one hand, efficient HLA-C expression enables the killing of infected cells by cytotoxic T lymphocytes (CTLs). On the other hand, HLA-C sends inhibitory signals to natural killer (NK) cells and enhances the infectivity of newly produced HIV particles. HIV-1 group M viruses modulate HLA-C expression using the accessory protein Vpu, possibly to balance CTL- and NK cell-mediated immune responses. Here, we show that the second human immunodeficiency virus, HIV-2, can use its accessory protein Vif to evade HLA-C-mediated restriction. Furthermore, our mutational analyses provide insights into the underlying molecular mechanisms. In summary, our results reveal how the two human AIDS viruses modulate HLA-C, a key component of the antiviral immune response.Kristina HopfenspergerJonathan RichardChristina M. StürzelFrederic Bibollet-RucheRichard AppsMarie LeozJean-Christophe PlantierBeatrice H. HahnAndrés FinziFrank KirchhoffDaniel SauterAmerican Society for MicrobiologyarticleHIV-1HIV-2SIVHLA-CVpuVifMicrobiologyQR1-502ENmBio, Vol 11, Iss 4 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	HIV-1 HIV-2 SIV HLA-C Vpu Vif Microbiology QR1-502
spellingShingle	HIV-1 HIV-2 SIV HLA-C Vpu Vif Microbiology QR1-502 Kristina Hopfensperger Jonathan Richard Christina M. Stürzel Frederic Bibollet-Ruche Richard Apps Marie Leoz Jean-Christophe Plantier Beatrice H. Hahn Andrés Finzi Frank Kirchhoff Daniel Sauter Convergent Evolution of HLA-C Downmodulation in HIV-1 and HIV-2
description	ABSTRACT HLA-C-mediated antigen presentation induces the killing of human immunodeficiency virus (HIV)-infected CD4+ T cells by cytotoxic T lymphocytes (CTLs). To evade killing, many HIV-1 group M strains decrease HLA-C surface levels using their accessory protein Vpu. However, some HIV-1 group M isolates lack this activity, possibly to prevent the activation of natural killer (NK) cells. Analyzing diverse primate lentiviruses, we found that Vpu-mediated HLA-C downregulation is not limited to pandemic group M but is also found in HIV-1 groups O and P as well as several simian immunodeficiency viruses (SIVs). We show that Vpu targets HLA-C primarily at the protein level, independently of its ability to suppress NF-κB-driven gene expression, and that in some viral lineages, HLA-C downregulation may come at the cost of efficient counteraction of the restriction factor tetherin. Remarkably, HIV-2, which does not carry a vpu gene, uses its accessory protein Vif to decrease HLA-C surface expression. This Vif activity requires intact binding sites for the Cullin5/Elongin ubiquitin ligase complex but is separable from its ability to counteract APOBEC3G. Similar to HIV-1 Vpu, the degree of HIV-2 Vif-mediated HLA-C downregulation varies considerably among different virus isolates. In agreement with opposing selection pressures in vivo, we show that the reduction of HLA-C surface levels by HIV-2 Vif is accompanied by increased NK cell-mediated killing. In summary, our results highlight the complex role of HLA-C in lentiviral infections and demonstrate that HIV-1 and HIV-2 have evolved at least two independent mechanisms to decrease HLA-C levels on infected cells. IMPORTANCE Genome-wide association studies suggest that HLA-C expression is a major determinant of viral load set points and CD4+ T cell counts in HIV-infected individuals. On the one hand, efficient HLA-C expression enables the killing of infected cells by cytotoxic T lymphocytes (CTLs). On the other hand, HLA-C sends inhibitory signals to natural killer (NK) cells and enhances the infectivity of newly produced HIV particles. HIV-1 group M viruses modulate HLA-C expression using the accessory protein Vpu, possibly to balance CTL- and NK cell-mediated immune responses. Here, we show that the second human immunodeficiency virus, HIV-2, can use its accessory protein Vif to evade HLA-C-mediated restriction. Furthermore, our mutational analyses provide insights into the underlying molecular mechanisms. In summary, our results reveal how the two human AIDS viruses modulate HLA-C, a key component of the antiviral immune response.
format	article
author	Kristina Hopfensperger Jonathan Richard Christina M. Stürzel Frederic Bibollet-Ruche Richard Apps Marie Leoz Jean-Christophe Plantier Beatrice H. Hahn Andrés Finzi Frank Kirchhoff Daniel Sauter
author_facet	Kristina Hopfensperger Jonathan Richard Christina M. Stürzel Frederic Bibollet-Ruche Richard Apps Marie Leoz Jean-Christophe Plantier Beatrice H. Hahn Andrés Finzi Frank Kirchhoff Daniel Sauter
author_sort	Kristina Hopfensperger
title	Convergent Evolution of HLA-C Downmodulation in HIV-1 and HIV-2
title_short	Convergent Evolution of HLA-C Downmodulation in HIV-1 and HIV-2
title_full	Convergent Evolution of HLA-C Downmodulation in HIV-1 and HIV-2
title_fullStr	Convergent Evolution of HLA-C Downmodulation in HIV-1 and HIV-2
title_full_unstemmed	Convergent Evolution of HLA-C Downmodulation in HIV-1 and HIV-2
title_sort	convergent evolution of hla-c downmodulation in hiv-1 and hiv-2
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/839388e6abb74760963d4aefd5626c6e
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Convergent Evolution of HLA-C Downmodulation in HIV-1 and HIV-2

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