Dataset Information

Impact of a single HLA-A24:02-associated escape mutation on the detrimental effect of HLA-B35:01 in HIV-1 control.

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.

SUBMITTER: Murakoshi H

PROVIDER: S-EPMC6197679 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Publications

Impact of a single HLA-A24:02-associated escape mutation on the detrimental effect of HLA-B35:01 in HIV-1 control.

Murakoshi Hayato H Koyanagi Madoka M Akahoshi Tomohiro T Chikata Takayuki T Kuse Nozomi N Gatanaga Hiroyuki H Rowland-Jones Sarah L SL Oka Shinichi S Takiguchi Masafumi M

EBioMedicine 20180922

<h4>Background</h4>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<sup>+</sup> T cells having abilities to suppress HIV-1 replication.<h4>Methods</h4> ...[more]

PMID: 30249546

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Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19) was announced as an outbreak by the World Health Organization (WHO) in January 2020 and as a pandemic in March 2020. The majority of infected individuals have experienced no or only mild symptoms, ranging from fully asymptomatic cases to mild pneumonic disease. However, a minority of infected individuals develop severe respiratory symptoms. The objective of this study was to identify susceptible HLA alleles and clinical markers that can be used in risk prediction model for the early identification of severe COVID-19 among hospitalized COVID-19 patients. A total of 137 patients with mild COVID-19 (mCOVID-19) and 53 patients with severe COVID-19 (sCOVID-19) were recruited from the Center Hospital of the National Center for Global Health and Medicine (NCGM), Tokyo, Japan for the period of February-August 2020. High-resolution sequencing-based typing for eight HLA genes was performed using next-generation sequencing. In the HLA association studies, HLA-A*11:01:01:01 [Pc = 0.013, OR = 2.26 (1.27-3.91)] and HLA-C*12:02:02:01-HLA-B*52:01:01:02 [Pc = 0.020, OR = 2.25 (1.24-3.92)] were found to be significantly associated with the severity of COVID-19. After multivariate analysis controlling for other confounding factors and comorbidities, HLA-A*11:01:01:01 [P = 3.34E-03, OR = 3.41 (1.50-7.73)], age at diagnosis [P = 1.29E-02, OR = 1.04 (1.01-1.07)] and sex at birth [P = 8.88E-03, OR = 2.92 (1.31-6.54)] remained significant. The area under the curve of the risk prediction model utilizing HLA-A*11:01:01:01, age at diagnosis, and sex at birth was 0.772, with sensitivity of 0.715 and specificity of 0.717. To the best of our knowledge, this is the first article that describes associations of HLA alleles with COVID-19 at the 4-field (highest) resolution level. Early identification of potential sCOVID-19 could help clinicians prioritize medical utility and significantly decrease mortality from COVID-19.

Project description:γδT cell receptors (γδTCRs) recognize a broad range of malignantly transformed cells in mainly a major histocompatibility complex (MHC)-independent manner, making them valuable additions to the engineered immune effector cell therapy that currently focuses primarily on αβTCRs and chimeric antigen receptors (CARs). As an exception to the rule, we have previously identified a γδTCR, which exerts antitumor reactivity against HLA-A*24:02-expressing malignant cells, however without the need for defined HLA-restricted peptides, and without exhibiting any sign of off-target toxicity in humanized HLA-A*24:02 transgenic NSG (NSG-A24:02) mouse models. This particular tumor-HLA-A*24:02-specific Vγ5Vδ1TCR required CD8αα co-receptor for its tumor reactive capacity when introduced into αβT cells engineered to express a defined γδTCR (TEG), referred to as TEG011; thus, it was only active in CD8+ TEG011. We subsequently explored the concept of additional redirection of CD4+ T cells through co-expression of the human CD8α gene into CD4+ and CD8+ TEG011 cells, later referred as TEG011_CD8α. Adoptive transfer of TEG011_CD8α cells in humanized HLA-A*24:02 transgenic NSG (NSG-A24:02) mice injected with tumor HLA-A*24:02+ cells showed superior tumor control in comparison to TEG011, and to mock control groups. The total percentage of mice with persisting TEG011_CD8α cells, as well as the total number of TEG011_CD8α cells per mice, was significantly improved over time, mainly due to a dominance of CD4+CD8+ double-positive TEG011_CD8α, which resulted in higher total counts of functional T cells in spleen and bone marrow. We observed that tumor clearance in the bone marrow of TEG011_CD8α-treated mice associated with better human T cell infiltration, which was not observed in the TEG011-treated group. Overall, introduction of transgenic human CD8α receptor on TEG011 improves antitumor reactivity against HLA-A*24:02+ tumor cells and further enhances in vivo tumor control.

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Dataset Information

Impact of a single HLA-A24:02-associated escape mutation on the detrimental effect of HLA-B35:01 in HIV-1 control.

Background

Methods

Findings

Interpretation

Publications

Impact of a single HLA-A24:02-associated escape mutation on the detrimental effect of HLA-B35:01 in HIV-1 control.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Impact of a single HLA-A*24:02-associated escape mutation on the detrimental effect of HLA-B*35:01 in HIV-1 control.

Background

Methods

Findings

Interpretation

Publications

Impact of a single HLA-A*24:02-associated escape mutation on the detrimental effect of HLA-B*35:01 in HIV-1 control.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Impact of a single HLA-A24:02-associated escape mutation on the detrimental effect of HLA-B35:01 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.