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A Critical Effect of Pol Escape Mutations Associated with a Detrimental Allele HLA-C*15:05 on Clinical Outcome in HIV-1 Subtype A/E Infection
42 Pages Posted: 7 Aug 2020
More...Abstract
Background: The mechanism explaining the role of detrimental HLA alleles in HIV-1 infections has not been studied. We recently demonstrated that HLA-A*29:01-B*07:05-C*15:05 is a detrimental haplotype and that Pol mutations associated with this haplotype significantly correlated with poor clinical outcome in HIV-1 subtype A/E-infected individuals. To clarify the mechanism underlying this detrimental haplotype, we here investigated the effect of these Pol mutations on the ability of HIV-1-specific CD8+ T-cells to recognize HIV-1 and on the clinical outcome.
Methods: To identify a T-cell epitope including Pol653/657 where this haplotype-associated mutations were found, we analyzed T-cell responses to overlapping or truncated peptides. The recognition of epitope-specific CD8+ T-cells were analyzed for target cells infected with the mutant virus. We further analyzed the existence of T-cells specific for this epitope and its mutant ones and their role in suppression of HIV-1 replication in the subtype A/E-infected HLA-C*15:05+ Vietnamese.
Findings: We identified HLA-C*15:05-restricted T-cells specific for the Pol SL9 epitope and found that 3 mutants (Pol S653A/T/L) had escaped from the T-cells. HLA-C*15:05+ individuals 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.
Interpretation: These findings indicate that the accumulation of Pol S653A/T/L mutants critically and negatively affected control of HIV-1 by SL9-specific T-cells in the subtype A/E-infected individuals having the HLA-C*15:05 detrimental allele.
Funding Statement: This research was supported by a grant-in-aid (15fk0410019) for AIDS Research from AMED, a JSPS KAKENHI grant-in-aid for scientific research (A) (grant No. 15H02658), and by a Joint Research Grant with the Institute of Tropical Medicine, Nagasaki University.
Declaration of Interests: The authors have no financial conflicts of interest.
Ethics Approval Statement: This study was approved by the Ethical Committee of NHTD and Kumamoto University. Informed consent was obtained from all individuals according to the Declaration of Helsinki.
Keywords: HIV-1; CTL; HLA-C*15:05; escape mutation
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