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

Murakoshi, Hayato; Koyanagi, Madoka; Akahoshi, Tomohiro; Chikata, Takayuki; Kuse, Nozomi; Gatanaga, Hiroyuki; Rowland‐Jones, Sarah; Oka, Shinichi; Takiguchi, Masafumi

doi:10.1016/j.ebiom.2018.09.022

Cited by 10 publications

(20 citation statements)

References 57 publications

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“…A longitudinal analysis of patient VI-065 also showed that the disease progression was associated with the accumulation of the L and T mutations and loss of SL9-1K-specific T cells. A similar mechanism was reported based on the study of the subtype B virus-infected Japanese individuals having a detrimental allele HLA-B∗35:01, which study showed that the Nef Y135F mutation selected by HLA-A∗24:02-restricted T cells impaired the TCR recognition and viral suppression ability of YF9-specific T cells restricted by HLA-B∗35:01 [ 31 ]. Both studies showed that the accumulation of escape mutations in the epitopes is a cause of a poor clinical outcome, whereas a different mechanism for the selection of escape mutations was found between the individuals having HLA-C∗15:05 and HLA-B∗35:01 detrimental alleles.…”

Section: Discussionsupporting

confidence: 66%

“…In contrast, little is known about the mechanism underlying the effects of detrimental alleles on disease outcome. A few studies proposed possible mechanisms for the detrimental effect of HLA-B∗35 [ 29 – 31 ]. Huang et al [ 29 ] demonstrated that strong binding of HLA-B∗35:03 molecules to immunoglobulin-like transcript 4 expressed on dendritic cells downregulated the expression of CD86 and HLA-DR and the secretion of IL-6, resulting in impaired dendritic cell function.…”

Section: Introductionmentioning

confidence: 99%

“…Matthews et al [ 30 ] showed that HLA-B∗35:01-restricted T cells specific for the Gag p24 NY10 epitope, which had the ability to suppress HIV-1 replication in vivo , were elicited among HIV-1 subtype C-infected HLA-B∗35:01 + individuals in Africa, where B∗35:01 is a neutral allele, whereas they were not found among the subtype B-infected HLA-B∗35:01 + patients in Mexico and Japan, where this allele is a detrimental one. In addition, a recent study demonstrated that the accumulation of the Y to F mutation at Nef135, which is selected by HLA-A∗24:02-restricted NefRF10-specific T cells, critically impairs the suppression of HIV-1 replication by HLA-B∗35:01-restricted NefYF9-specific T cells in HIV-infected Japanese individuals, suggesting that the accumulation of a single escape mutation is a key factor for the detrimental effect of HLA-B∗35:01 on clinical outcome in Japanese [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

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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

Chikata

Akahoshi

et al. 2020

Aids

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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.

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Section: Discussionsupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

Chikata

Akahoshi

et al. 2020

Aids

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“…As immune escape mutations compromise the recognition of HIV-1 by virus-specific T cells, their accumulation at the population level compromises T cell-mediated control of HIV-1 [10,[20][21][22][23]. These negative implications also extend to protective HLA alleles such as HLA-B57, HLA-B27, and HLA-B51 [6,[24][25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

T-cell responses to sequentially emerging viral escape mutants shape long-term HIV-1 population dynamics

et al. 2020

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HIV-1 strains harboring immune escape mutations can persist in circulation, but the impact of selection by multiple HLA alleles on population HIV-1 dynamics remains unclear. In Japan, HIV-1 Reverse Transcriptase codon 135 (RT135) is under strong immune pressure by HLA-B*51:01-restricted and HLA-B*52:01-restricted T cells that target a key epitope in this region (TI8; spanning RT codons 128–135). Major population-level shifts have occurred at HIV-1 RT135 during the Japanese epidemic, which first affected hemophiliacs (via imported contaminated blood products) and subsequently non-hemophiliacs (via domestic transmission). Specifically, threonine accumulated at RT135 (RT135T) in hemophiliac and non-hemophiliac HLA-B*51:01+ individuals diagnosed before 1997, but since then RT135T has markedly declined while RT135L has increased among non-hemophiliac individuals. We demonstrated that RT135V selection by HLA-B*52:01-restricted TI8-specific T-cells led to the creation of a new HLA-C*12:02-restricted epitope TN9-8V. We further showed that TN9-8V-specific HLA-C*12:02-restricted T cells selected RT135L while TN9-8T-specific HLA-C*12:02-restricted T cells suppressed replication of the RT135T variant. Thus, population-level accumulation of the RT135L mutation over time in Japan can be explained by initial targeting of the TI8 epitope by HLA-B*52:01-restricted T-cells, followed by targeting of the resulting escape mutant by HLA-C*12:02-restricted T-cells. We further demonstrate that this phenomenon is particular to Japan, where the HLA-B*52:01-C*12:02 haplotype is common: RT135L did not accumulate over a 15-year longitudinal analysis of HIV sequences in British Columbia, Canada, where this haplotype is rare. Together, our observations reveal that T-cell responses to sequentially emerging viral escape mutants can shape long-term HIV-1 population dynamics in a host population-specific manner.

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“…HLA class I alleles or haplotypes have consistently been shown to have a significant impact on the rate of HIV-1 disease progression to AIDS (26)(27)(28)(29)(30)(31)(32)(33)(34). HLA-B*57, HLA-B*27, and HLA-B*52 are associated with a slow progression to AIDS (26,27,31,(33)(34)(35)(36), whereas HLA-B*35, HLA-B*58:02, and HLA-A*29:01-B*07:05-C*15:05 are associated with a rapid progression (28,32,34,(37)(38)(39)(40). Whole-genome association analyses confirmed that HLA-B*57 and HLA-B*52:01 are the first and second strongest protective alleles, respectively, in Caucasian and/or African individuals (33,40).…”

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confidence: 99%

Role of Escape Mutant-Specific T Cells in Suppression of HIV-1 Replication and Coevolution with HIV-1

Zhang

Kuse

Akahoshi

et al. 2020

J Virol

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The accumulation of HIV-1 escape mutations affects HIV-1 control by HIV-1-specific T cells. Some of these mutations can elicit escape mutant-specific T-cells, but it still remains unclear whether they can suppress the replication of HIV-1 mutant viruses. It is known that HLA-B*52:01-restricted RI8 (Gag 275-282, RMYSPTSI) is a protective T cell epitope in HIV-1 subtype B-infected Japanese individuals, though 3 Gag280A/S/V mutations are found in 26% of them. Gag280S and Gag280A were HLA-B*52:01-associated mutations; whereas Gag280V was not, implying a different mechanism for the accumulation of Gag280 mutations. We here investigated the co-evolution of HIV-1 with RI8-specific T-cells and suppression of HIV-1 replication by its escape mutant-specific T-cells both in vitro and in vivo. The HLA-B*52:01+ individuals infected with Gag280A/S mutant viruses failed to elicit these mutant epitope-specific T-cells, whereas those with the Gag280V mutant one effectively elicited RI8-6V mutant-specific T-cells. These RI8-6V-specific T cells suppressed the replication of Gag280V virus and selected wild-type virus, suggesting a mechanism affording no accumulation of the Gag280V mutation in the HLA-B*52:01+ individuals. The responders to wild-type (RI8-6T) and RI8-6V mutant peptides had significantly higher CD4 counts than non-responders, indicating that the existence of not only RI8-6T-specific T cells but also RI8-6V-specific ones was associated with a good clinical outcome. The present study clarified the role of escape mutant-specific T cells in HIV-1 evolution and in the control of HIV-1. Importance Escape mutant-specific CD8+ T-cells were elicited in some individuals infected with escape mutants, but it is still unknown that these CD8+ T-cells can suppress HIV-1 replication. We clarified that Gag280V mutation were selected by HLA-B*52:01-restricted CD8+ T-cells specific for GagRI8 protective epitope whereas the Gag280V virus could frequently elicit GagRI8-6V mutant-specific CD8+ T-cells. GagRI8-6V mutant-specific T-cells had a strong ability to suppress the replication of the Gag280V mutant virus both in vitro and in vivo. In addition, these T cells contributed to the selection of wild-type virus in HLA-B*52:01+ Japanese individuals. We for the first time demonstrated that escape mutant-specific CD8+ T-cells can suppress HIV-1 replication and play an important role in the coevolution with HIV-1. Thus, the present study highlighted an important role of escape mutant-specific T-cells in the control of HIV-1 and co-evolution with HIV-1.

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

Cited by 10 publications

References 57 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

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

T-cell responses to sequentially emerging viral escape mutants shape long-term HIV-1 population dynamics

Role of Escape Mutant-Specific T Cells in Suppression of HIV-1 Replication and Coevolution with HIV-1

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