Dataset Information

Critical effect of Pol escape mutations associated with detrimental allele HLA-C*15: 05 on clinical outcome in HIV-1 subtype A/E infection.

ABSTRACT:

Objective

The mechanism explaining the role of detrimental HLA alleles in HIV-1 infections has been investigated in very few studies. HLA-A*29:01-B*07:05-C*15:05 is a detrimental haplotype in HIV-1 subtype A/E-infected Vietnamese individuals. The accumulation of mutations at Pol 653/657 is associated with a poor clinical outcome in these individuals. However, the detrimental HLA allele and the mechanism responsible for its detrimental effect remains unknown. Therefore, in this current study we identified the detrimental HLA allele and investigated the mechanism responsible for the detrimental effect.

Design and methods

A T-cell epitope including Pol 653/657 and its HLA restriction were identified by using overlapping HIV-1 peptides and cell lines expressing a single HLA. The effect of the mutations on the T-cell recognition of HIV-1-infected cells was investigated by using target cells infected with the mutant viruses. The effect of these mutations on the clinical outcome was analyzed in 74 HLA-C*15:05 Vietnamese infected with the subtype A/E virus.

Results

We identified HLA-C*15:05-restricted SL9 epitope including Pol 653/657. PolS653A/T/L mutations within this epitope critically impaired the T-cell recognition of HIV-1-infected cells, indicating that these mutations had escaped from the T cells. T-cell responders infected with these mutants showed significantly lower CD4 T-cell counts than those with the wild-type virus or Pol S653K/Q mutants, which are not associated with HLA-C*15:05.

Conclusion

The accumulation of Pol S653A/T/L escape mutants critically affected the control of HIV-1 by SL9-specific T cells and led to a poor clinical outcome in the subtype A/E-infected individuals having the detrimental HLA-C*15:05 allele.

SUBMITTER: Murakoshi H

PROVIDER: S-EPMC7752225 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Critical effect of Pol escape mutations associated with detrimental allele HLA-C*15: 05 on clinical outcome in HIV-1 subtype A/E infection.

Murakoshi Hayato H Chikata Takayuki T Akahoshi Tomohiro T Zou Chengcheng C Borghan Mohamed Ali MA Van Tran Giang G Nguyen Trung Vu TV Van Nguyen Kinh K Kuse Nozomi N Takiguchi Masafumi M

AIDS (London, England) 20210101 1

<h4>Objective</h4>The mechanism explaining the role of detrimental HLA alleles in HIV-1 infections has been investigated in very few studies. HLA-A*29:01-B*07:05-C*15:05 is a detrimental haplotype in HIV-1 subtype A/E-infected Vietnamese individuals. The accumulation of mutations at Pol 653/657 is associated with a poor clinical outcome in these individuals. However, the detrimental HLA allele and the mechanism responsible for its detrimental effect remains unknown. Therefore, in this current st ...[more]

PMID: 33031103

Similar Datasets

Project description:BACKGROUND:Despite the extensive genetic diversity of HIV-1, viral evolution in response to immune selective pressures follows broadly predictable mutational patterns. Sites and pathways of Human Leukocyte-Antigen (HLA)-associated polymorphisms in HIV-1 have been identified through the analysis of population-level data, but the full extent of immune escape pathways remains incompletely characterized. Here, in the largest analysis of HIV-1 subtype B sequences undertaken to date, we identify HLA-associated polymorphisms in the three HIV-1 proteins most commonly considered in cellular-based vaccine strategies. Results are organized into protein-wide escape maps illustrating the sites and pathways of HLA-driven viral evolution. METHODOLOGY/PRINCIPAL FINDINGS:HLA-associated polymorphisms were identified in HIV-1 Gag, Pol and Nef in a multicenter cohort of >1500 chronically subtype-B infected, treatment-naïve individuals from established cohorts in Canada, the USA and Western Australia. At q< or =0.05, 282 codons commonly mutating under HLA-associated immune pressures were identified in these three proteins. The greatest density of associations was observed in Nef (where close to 40% of codons exhibited a significant HLA association), followed by Gag then Pol (where approximately 15-20% of codons exhibited HLA associations), confirming the extensive impact of immune selection on HIV evolution and diversity. Analysis of HIV codon covariation patterns identified over 2000 codon-codon interactions at q< or =0.05, illustrating the dense and complex networks of linked escape and secondary/compensatory mutations. CONCLUSIONS/SIGNIFICANCE:The immune escape maps and associated data are intended to serve as a user-friendly guide to the locations of common escape mutations and covarying codons in HIV-1 subtype B, and as a resource facilitating the systematic identification and classification of immune escape mutations. These resources should facilitate research in HIV epitope discovery and host-pathogen co-evolution, and are relevant to the continued search for an effective CTL-based AIDS vaccine.

Dataset Information

Critical effect of Pol escape mutations associated with detrimental allele HLA-C*15: 05 on clinical outcome in HIV-1 subtype A/E infection.

Objective

Design and methods

Results

Conclusion

Publications

Critical effect of Pol escape mutations associated with detrimental allele HLA-C*15: 05 on clinical outcome in HIV-1 subtype A/E infection.

Similar Datasets

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