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Relative Resistance of HLA-B to Downregulation by Naturally Occurring HIV-1 Nef Sequences
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 effe...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Microbiology
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724998/ https://www.ncbi.nlm.nih.gov/pubmed/26787826 http://dx.doi.org/10.1128/mBio.01516-15 |
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author | Mahiti, Macdonald Toyoda, Mako Jia, Xiaofei Kuang, Xiaomei T. Mwimanzi, Francis Mwimanzi, Philip Walker, Bruce D. Xiong, Yong Brumme, Zabrina L. Brockman, Mark A. Ueno, Takamasa |
author_facet | Mahiti, Macdonald Toyoda, Mako Jia, Xiaofei Kuang, Xiaomei T. Mwimanzi, Francis Mwimanzi, Philip Walker, Bruce D. Xiong, Yong Brumme, Zabrina L. Brockman, Mark A. Ueno, Takamasa |
author_sort | Mahiti, Macdonald |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4724998 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | American Society of Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-47249982016-01-28 Relative Resistance of HLA-B to Downregulation by Naturally Occurring HIV-1 Nef Sequences Mahiti, Macdonald Toyoda, Mako Jia, Xiaofei Kuang, Xiaomei T. Mwimanzi, Francis Mwimanzi, Philip Walker, Bruce D. Xiong, Yong Brumme, Zabrina L. Brockman, Mark A. Ueno, Takamasa mBio Research Article 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. American Society of Microbiology 2016-01-19 /pmc/articles/PMC4724998/ /pubmed/26787826 http://dx.doi.org/10.1128/mBio.01516-15 Text en Copyright © 2016 Mahiti et al. http://creativecommons.org/licenses/by-nc-sa/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license (http://creativecommons.org/licenses/by-nc-sa/3.0/) , which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Mahiti, Macdonald Toyoda, Mako Jia, Xiaofei Kuang, Xiaomei T. Mwimanzi, Francis Mwimanzi, Philip Walker, Bruce D. Xiong, Yong Brumme, Zabrina L. Brockman, Mark A. Ueno, Takamasa Relative Resistance of HLA-B to Downregulation by Naturally Occurring HIV-1 Nef Sequences |
title | 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_short | 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 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724998/ https://www.ncbi.nlm.nih.gov/pubmed/26787826 http://dx.doi.org/10.1128/mBio.01516-15 |
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