Impact of a Single HLA-A24:02-associated Escape Mutation on the Detrimental Effect of HLA-B35:01 in HIV-1 Control

Overview

Journal EBioMedicine

Specialty Biomedical Engineering

Date 2018 Sep 26

PMID 30249546

Citations 9

Authors

Hayato Murakoshi

Madoka Koyanagi

Tomohiro Akahoshi

Takayuki Chikata

Nozomi Kuse

Hiroyuki Gatanaga

Sarah L Rowland-Jones

Shinichi Oka

Masafumi Takiguchi

Affiliations

Soon will be listed here.

Abstract

Background: HLA-B*35 is an HLA allele associated with rapid progression to AIDS. However, a mechanism underlying the detrimental effect of HLA-B*35 on disease outcome remains unknown. Recent studies demonstrated that most prevalent subtype HLA-B*35:01 is a detrimental allele in HIV-1 clade B-infected individuals. We here investigated the effect of mutations within the epitopes on HLA-B*35:01-restricted CD8 T cells having abilities to suppress HIV-1 replication.

Methods: We analyzed 16 HLA-B*35:01-restricted epitope-specific T cells in 63 HIV-1 clade B-infected Japanese B*35:01 individuals and identified HLA-B*35:01-restricted CD8 T cells having abilities to suppress HIV-1 replication. We further analyzed the effect of HLA-associated mutations on the ability of these T cells.

Findings: The breadth of T cell responses to 4 epitopes was inversely associated with plasma viral load (pVL). However, the accumulation of an Y135F mutation in NefYF9 out of the 4 epitopes, which is selected by HLA-A*24:02-restricted T cells, affected the ability of YF9-specific T cells to suppress HIV-1 replication. HLA-B*35:01 individuals harboring this mutation had much higher pVL than those without it. YF9-specific T cells failed to suppress replication of the Y135F mutant in vitro. These results indicate that this mutation impairs suppression of HIV-1 replication by YF9-specific T cells.

Interpretation: These findings indicate that the Y135F mutation is a key factor underlying the detrimental effect of HLA-B*35:01 on disease outcomes in HIV-1 clade B-infected individuals. FUND: Grants-in-aid for AIDS Research from AMED and for scientific research from the Ministry of Education, Science, Sports, and Culture, Japan.

Citing Articles

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PMID: 37877716 PMC: 10688310. DOI: 10.1128/jvi.01024-23.

Molecular insights into the HLA-B35 molecules' classification associated with HIV control.

Lobos C, Chatzileontiadou D, Sok B, Almedia C, Halim H, DOrsogna L Immunol Cell Biol. 2023; 102(1):34-45.

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Valenzuela-Fernandez A, Cabrera-Rodriguez R, Casado C, Perez-Yanes S, Pernas M, Garcia-Luis J Biomedicines. 2022; 10(9).

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HLA-B*13, B*35 and B*39 Alleles Are Closely Associated With the Lack of Response to ART in HIV Infection: A Cohort Study in a Population of Northern Brazil.

Pereira L, Franca E, Costa I, Jorge E, de Souza Mendonca Mattos P, Freire A Front Immunol. 2022; 13:829126.

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Association between low levels of HIV-1 DNA and HLA class I molecules in chronic HIV-1 infection.

Muccini C, Guffanti M, Spagnuolo V, Cernuschi M, Galli L, Bigoloni A PLoS One. 2022; 17(3):e0265348.

PMID: 35290394 PMC: 8923435. DOI: 10.1371/journal.pone.0265348.

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Impact of a Single HLA-A*24:02-associated Escape Mutation on the Detrimental Effect of HLA-B*35:01 in HIV-1 Control

Impact of a Single HLA-A24:02-associated Escape Mutation on the Detrimental Effect of HLA-B35:01 in HIV-1 Control