Relative Resistance of HLA-B to Downregulation by Naturally Occurring HIV-1 Nef Sequences

ABSTRACT HIV-1 Nef binds to the cytoplasmic region of HLA-A and HLA-B and downregulates these molecules from the surface of virus-infected cells, thus evading immune detection by CD8+ T cells. Polymorphic residues within the HLA cytoplasmic region may affect Nef’s downregulation activity. However, t...

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Autores principales:	Macdonald Mahiti, Mako Toyoda, Xiaofei Jia, Xiaomei T. Kuang, Francis Mwimanzi, Philip Mwimanzi, Bruce D. Walker, Yong Xiong, Zabrina L. Brumme, Mark A. Brockman, Takamasa Ueno
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Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/89ef5bd0118b44c7bdbff19549c0ad89
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spelling	oai:doaj.org-article:89ef5bd0118b44c7bdbff19549c0ad892021-11-15T15:49:40ZRelative Resistance of HLA-B to Downregulation by Naturally Occurring HIV-1 Nef Sequences10.1128/mBio.01516-152150-7511https://doaj.org/article/89ef5bd0118b44c7bdbff19549c0ad892016-03-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01516-15https://doaj.org/toc/2150-7511ABSTRACT HIV-1 Nef binds to the cytoplasmic region of HLA-A and HLA-B and downregulates these molecules from the surface of virus-infected cells, thus evading immune detection by CD8+ T cells. Polymorphic residues within the HLA cytoplasmic region may affect Nef’s downregulation activity. However, the effects of HLA polymorphisms on recognition by primary Nef isolates remain elusive, as do the specific Nef regions responsible for downregulation of HLA-A versus HLA-B. Here, we examined 46 Nef clones isolated from chronically HIV-1 subtype B-infected subjects for their ability to downregulate various HLA-A, HLA-B, and HLA-C molecules on the surface of virus-infected cells. Overall, HLA-B exhibited greater resistance to Nef-mediated downregulation than HLA-A, regardless of the cell type examined. As expected, no Nef clone downregulated HLA-C. Importantly, the differential abilities of patient-derived Nef clones to downregulate HLA-A and HLA-B correlated inversely with the sensitivities of HIV-infected target cells to recognition by effector cells expressing an HIV-1 Gag-specific T cell receptor. Nef codon function analysis implicated amino acid variation at position 202 (Nef-202) in differentially affecting the ability to downregulate HLA-A and HLA-B, an observation that was subsequently confirmed by experiments using Nef mutants constructed by site-directed mutagenesis. The in silico and mutagenesis analyses further suggested that Nef-202 may interact with the C-terminal Cys-Lys-Val residues of HLA-A, which are absent in HLA-B. Taken together, the results show that natural polymorphisms within Nef modulate its interaction with natural polymorphisms in the HLA cytoplasmic tails, thereby affecting the efficiency of HLA downregulation and consequent recognition by HIV-specific T cells. These results thus extend our understanding of this complex pathway of retroviral immune evasion. IMPORTANCE Recognition of genetically diverse pathogens by the adaptive immune system represents a primary strategy for host defense; however, pathogens such as HIV-1 can evade these responses to achieve persistent infection. The HIV-1 nef gene and the HLA class I locus rank among the most diverse genes of virus and host, respectively. The HIV-1 Nef protein interacts with the cytoplasmic region of HLA-A and HLA-B and downregulates these molecules to evade cellular immunity. By combining molecular, genetic, and in silico analyses, we demonstrate that patient-derived Nef clones downregulate HLA-A more effectively than HLA-B molecules. This in turn modulates the ability of HIV-specific T cells to recognize HIV-infected cells. We also identify a naturally polymorphic site at Nef codon 202 and HLA cytoplasmic motifs (GG314,315 and CKV339–341) that contribute to differential HLA downregulation by Nef. Our results highlight new interactions between HIV-1 and the human immune system that may contribute to pathogenesis.Macdonald MahitiMako ToyodaXiaofei JiaXiaomei T. KuangFrancis MwimanziPhilip MwimanziBruce D. WalkerYong XiongZabrina L. BrummeMark A. BrockmanTakamasa UenoAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 1 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Macdonald Mahiti Mako Toyoda Xiaofei Jia Xiaomei T. Kuang Francis Mwimanzi Philip Mwimanzi Bruce D. Walker Yong Xiong Zabrina L. Brumme Mark A. Brockman Takamasa Ueno Relative Resistance of HLA-B to Downregulation by Naturally Occurring HIV-1 Nef Sequences
description	ABSTRACT HIV-1 Nef binds to the cytoplasmic region of HLA-A and HLA-B and downregulates these molecules from the surface of virus-infected cells, thus evading immune detection by CD8+ T cells. Polymorphic residues within the HLA cytoplasmic region may affect Nef’s downregulation activity. However, the effects of HLA polymorphisms on recognition by primary Nef isolates remain elusive, as do the specific Nef regions responsible for downregulation of HLA-A versus HLA-B. Here, we examined 46 Nef clones isolated from chronically HIV-1 subtype B-infected subjects for their ability to downregulate various HLA-A, HLA-B, and HLA-C molecules on the surface of virus-infected cells. Overall, HLA-B exhibited greater resistance to Nef-mediated downregulation than HLA-A, regardless of the cell type examined. As expected, no Nef clone downregulated HLA-C. Importantly, the differential abilities of patient-derived Nef clones to downregulate HLA-A and HLA-B correlated inversely with the sensitivities of HIV-infected target cells to recognition by effector cells expressing an HIV-1 Gag-specific T cell receptor. Nef codon function analysis implicated amino acid variation at position 202 (Nef-202) in differentially affecting the ability to downregulate HLA-A and HLA-B, an observation that was subsequently confirmed by experiments using Nef mutants constructed by site-directed mutagenesis. The in silico and mutagenesis analyses further suggested that Nef-202 may interact with the C-terminal Cys-Lys-Val residues of HLA-A, which are absent in HLA-B. Taken together, the results show that natural polymorphisms within Nef modulate its interaction with natural polymorphisms in the HLA cytoplasmic tails, thereby affecting the efficiency of HLA downregulation and consequent recognition by HIV-specific T cells. These results thus extend our understanding of this complex pathway of retroviral immune evasion. IMPORTANCE Recognition of genetically diverse pathogens by the adaptive immune system represents a primary strategy for host defense; however, pathogens such as HIV-1 can evade these responses to achieve persistent infection. The HIV-1 nef gene and the HLA class I locus rank among the most diverse genes of virus and host, respectively. The HIV-1 Nef protein interacts with the cytoplasmic region of HLA-A and HLA-B and downregulates these molecules to evade cellular immunity. By combining molecular, genetic, and in silico analyses, we demonstrate that patient-derived Nef clones downregulate HLA-A more effectively than HLA-B molecules. This in turn modulates the ability of HIV-specific T cells to recognize HIV-infected cells. We also identify a naturally polymorphic site at Nef codon 202 and HLA cytoplasmic motifs (GG314,315 and CKV339–341) that contribute to differential HLA downregulation by Nef. Our results highlight new interactions between HIV-1 and the human immune system that may contribute to pathogenesis.
format	article
author	Macdonald Mahiti Mako Toyoda Xiaofei Jia Xiaomei T. Kuang Francis Mwimanzi Philip Mwimanzi Bruce D. Walker Yong Xiong Zabrina L. Brumme Mark A. Brockman Takamasa Ueno
author_facet	Macdonald Mahiti Mako Toyoda Xiaofei Jia Xiaomei T. Kuang Francis Mwimanzi Philip Mwimanzi Bruce D. Walker Yong Xiong Zabrina L. Brumme Mark A. Brockman Takamasa Ueno
author_sort	Macdonald Mahiti
title	Relative Resistance of HLA-B to Downregulation by Naturally Occurring HIV-1 Nef Sequences
title_short	Relative Resistance of HLA-B to Downregulation by Naturally Occurring HIV-1 Nef Sequences
title_full	Relative Resistance of HLA-B to Downregulation by Naturally Occurring HIV-1 Nef Sequences
title_fullStr	Relative Resistance of HLA-B to Downregulation by Naturally Occurring HIV-1 Nef Sequences
title_full_unstemmed	Relative Resistance of HLA-B to Downregulation by Naturally Occurring HIV-1 Nef Sequences
title_sort	relative resistance of hla-b to downregulation by naturally occurring hiv-1 nef sequences
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/89ef5bd0118b44c7bdbff19549c0ad89
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Relative Resistance of HLA-B to Downregulation by Naturally Occurring HIV-1 Nef Sequences

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