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

Akahoshi, Tomohiro; Gatanaga, Hiroyuki; Kuse, Nozomi; Chikata, Takayuki; Koyanagi, Madoka; Ishizuka, Naoki; Brumme, Chanson J.; Murakoshi, Hayato; Brumme, Zabrina L.; Oka, Shinichi; Takiguchi, Masafumi

doi:10.1371/journal.ppat.1009177

Cited by 4 publications

(5 citation statements)

References 60 publications

(97 reference statements)

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“…More than 0.01% of tetramer + CD8 + cells were evaluated as positive values for tetramer staining. Frequencies of tetramer + CD8 + T cells among PBMCs from HIV-1-uninfected individuals were similar to that among tetramer-unstained PBMCs from HIV-1-infected individuals as described previously ( 25 ).…”

Section: Methodssupporting

confidence: 57%

“…Therefore, escape mutant-specific T cells are elicited rarely in individuals infected with escape mutant viruses. Recent studies reported some cases in which T cells specific for HIV-1 escape mutations or HLA-associated mutations were elicited in individuals infected with viruses expressing an escape- or HLA-associated mutation ( 11 , 18 , 20 – 25 ). However, these T cells show no or a very limited ability to suppress the replication of mutant viruses in vitro ( 7 , 11 , 19 ), suggesting that these T cells would also not be able to suppress HIV-1 replication in vivo .…”

Section: Introductionmentioning

confidence: 99%

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Collaboration of a Detrimental HLA-B35:01 Allele with HLA-A24:02 in Coevolution of HIV-1 with T Cells Leading to Poorer Clinical Outcomes

Kuse

Murakoshi

Akahoshi

et al. 2021

J Virol

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Although mutant-specific T-cells are elicited in some individuals infected with HIV-1 mutant viruses, the detailed characteristics of these T-cells remain unknown. A recent study showed that the accumulation of strains expressing Nef135F, which were selected by HLA-A*24:02-restricted T-cells, was associated with poor outcomes in individuals with the detrimental HLA-B*35:01 allele, and that HLA-B*35:01-restricted NefYF9(Nef135-143)-specific T-cells failed to recognize target cells infected with Nef135F mutant viruses. Here we investigated HLA-B*35:01-restricted T-cells specific for the NefFF9 epitope incorporating the Nef135F mutation. Longitudinal TCR clonotype analysis demonstrated that 3 types of HLA-B*35:01-restricted T-cells (wild type-specific, mutant-specific, and cross-reactive) with different T-cell repertoires were elicited during the clinical course. HLA-B*35:01 + individuals possessing wild type-specific T-cells had a significantly lower pVL than those with mutant-specific and/or cross-reactive T-cells, even though the latter T-cells effectively recognized the mutant virus-infected cells. These results suggest that mutant-specific and cross-reactive T-cells could only partially suppress HIV-1 replication in vivo. Ex vivo analysis of the T-cells showed higher expression of PD-1 on cross-reactive T-cells and lower expression of CD160/2B4 on the mutant-specific T cells than other T-cells, implying that these inhibitory and stimulatory molecules are key to the reduced function of these T-cells. In the present study, we demonstrate that mutant-specific and cross-reactive T-cells do not contribute to suppression of HIV-1 replication in HIV-1-infected individuals, even though they have the capacity to recognize mutant virus-infected cells. Thus, the collaboration of HLA-A*24:02 with the detrimental allele HLA-B*35:01 resulted in the co-evolution of HIV-1 alongside virus-specific T-cells, leading to poorer clinical outcomes. Importance HIV-1 escape mutations are selected under pressure from HIV-1-specific CD8 + T-cells. Accumulation of these mutations in circulating viruses impairs control of HIV-1 by HIV-1-specific T-cells. Although it is known that HIV-1-specific T-cells recognizing mutant virus were elicited in some individuals infected with mutant virus, the role of these T-cells remains unclear. Accumulation of Phenylalanine at HIV-1 Nef135 (Nef135F), which is selected by HLA-A*24:02-restricted T-cells, led to poor clinical outcome in individuals carrying the detrimental HLA-B*35:01 allele. In the present study, we found that HLA-B*35:01-restricted mutant-specific and cross-reactive T-cells were elicited in HLA-B*35:01 + individuals infected with Nef135F mutant virus. These T-cells could not effectively suppress HIV-1 replication in vivo even though they could recognize mutant virus-infected cells in vitro . Mutant-specific and cross-reactive T-cells expressed lower levels of stimulatory molecules and higher levels of inhibitory molecules, respectively, suggesting a potential mechanism whereby these T-cells fail to suppress HIV-1 replication in HIV-1-infected individuals.

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Section: Methodssupporting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Collaboration of a Detrimental HLA-B35:01 Allele with HLA-A24:02 in Coevolution of HIV-1 with T Cells Leading to Poorer Clinical Outcomes

Kuse

Murakoshi

Akahoshi

et al. 2021

J Virol

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“…In silico analysis identified a high affinity for potential T-cell epitopes of S-protein ( 74 ). Previous studies reported a protective role of B*51:01 in the long-term control of AIDS progression in HIV-infected individuals ( 75 – 77 ). The alternative allele B*07:02, co-expressed with B*51:01, had a beneficial association with high antiviral efficacy against SARS-CoV-2 ( 78 ).…”

Section: Discussionmentioning

confidence: 92%

Differential haplotype expression in class I MHC genes during SARS-CoV-2 infection of human lung cell lines

et al. 2023

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IntroductionCell entry of SARS-CoV-2 causes genome-wide disruption of the transcriptional profiles of genes and biological pathways involved in the pathogenesis of COVID-19. Expression allelic imbalance is characterized by a deviation from the Mendelian expected 1:1 expression ratio and is an important source of allele-specific heterogeneity. Expression allelic imbalance can be measured by allele-specific expression analysis (ASE) across heterozygous informative expressed single nucleotide variants (eSNVs). ASE reflects many regulatory biological phenomena that can be assessed by combining genome and transcriptome information. ASE contributes to the interindividual variability associated with the disease. We aim to estimate the transcriptome-wide impact of SARS-CoV-2 infection by analyzing eSNVs.MethodsWe compared ASE profiles in the human lung cell lines Calu-3, A459, and H522 before and after infection with SARS-CoV-2 using RNA-Seq experiments.ResultsWe identified 34 differential ASE (DASE) sites in 13 genes (HLA-A, HLA-B, HLA-C, BRD2, EHD2, GFM2, GSPT1, HAVCR1, MAT2A, NQO2, SUPT6H, TNFRSF11A, UMPS), all of which are enriched in protein binding functions and play a role in COVID-19. Most DASE sites were assigned to the MHC class I locus and were predominantly upregulated upon infection. DASE sites in the MHC class I locus also occur in iPSC-derived airway epithelium basal cells infected with SARS-CoV-2. Using an RNA-Seq haplotype reconstruction approach, we found DASE sites and adjacent eSNVs in phase (i.e., predicted on the same DNA strand), demonstrating differential haplotype expression upon infection. We found a bias towards the expression of the HLA alleles with a higher binding affinity to SARS-CoV-2 epitopes.DiscussionIndependent of gene expression compensation, SARS-CoV-2 infection of human lung cell lines induces transcriptional allelic switching at the MHC loci. This suggests a response mechanism to SARS-CoV-2 infection that swaps HLA alleles with poor epitope binding affinity, an expectation supported by publicly available proteome data.

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“…In silico analysis identified a high affinity for potential T-cell epitopes of S-protein (64). Previous studies reported a protective role of B*51:01 in the long-term control of AIDS progression in HIV-infected individuals (65–67). The alternative allele B*07:02, co-expressed with B*51:01, had a beneficial association with high antiviral efficacy against SARS-CoV-2 (68).…”

Section: Discussionmentioning

confidence: 92%

Differential haplotype expression in class I MHC genes during SARS-CoV-2 infection of human lung cell lines

Francisco

Temerozo

Ferreira

et al. 2022

Preprint

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Cell entry of SARS-CoV-2 causes genome-wide disruption of the transcriptional profiles of genes and biological pathways involved in the pathogenesis of COVID-19. Expression allelic imbalance is characterized by a deviation from the Mendelian expected 1:1 expression ratio and is an important source of allele-specific heterogeneity. Expression allelic imbalance can be measured by allele-specific expression analysis (ASE) across heterozygous informative expressed single nucleotide variants (eSNVs). ASE reflects many regulatory biological phenomena that can be assessed by combining genome and transcriptome information. ASE contributes to the interindividual variability associated with disease. We aim to estimate the transcriptome-wide impact of SARS-CoV-2 infection by analyzing eSNVs. We compared ASE profiles in the human lung cell lines Calu-3, A459, and H522 before and after infection with SARS-CoV-2 using RNA-Seq experiments. We identified 34 differential ASE (DASE) sites in 13 genes (HLA-A, HLA-B, HLA-C, BRD2, EHD2, GFM2, GSPT1, HAVCR1, MAT2A, NQO2, SUPT6H, TNFRSF11A, UMPS), all of which are enriched in protein binding functions and play a role in COVID-19. Most DASE sites were assigned to the MHC class I locus and were predominantly upregulated upon infection. DASE sites in the MHC class I locus also occur in iPSC-derived airway epithelium basal cells infected with SARS-CoV-2. Using an RNA-Seq haplotype reconstruction approach, we found DASE sites and adjacent eSNVs in phase (i.e., predicted on the same DNA strand), demonstrating differential haplotype expression upon infection. We found a bias towards the expression of the HLA alleles with a higher binding affinity to SARS-CoV-2 epitopes. Independent of gene expression compensation, SARS-CoV-2 infection of human lung cell lines induces transcriptional allelic switching at the MHC loci. This suggests a response mechanism to SARS-CoV-2 infection that swaps HLA alleles with poor epitope binding affinity, an expectation supported by publicly available proteome data.

show abstract

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

Cited by 4 publications

References 60 publications

Collaboration of a Detrimental HLA-B35:01 Allele with HLA-A24:02 in Coevolution of HIV-1 with T Cells Leading to Poorer Clinical Outcomes

Collaboration of a Detrimental HLA-B35:01 Allele with HLA-A24:02 in Coevolution of HIV-1 with T Cells Leading to Poorer Clinical Outcomes

Differential haplotype expression in class I MHC genes during SARS-CoV-2 infection of human lung cell lines

Differential haplotype expression in class I MHC genes during SARS-CoV-2 infection of human lung cell lines

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

Cited by 4 publications

References 60 publications

Collaboration of a Detrimental HLA-B*35:01 Allele with HLA-A*24:02 in Coevolution of HIV-1 with T Cells Leading to Poorer Clinical Outcomes

Collaboration of a Detrimental HLA-B*35:01 Allele with HLA-A*24:02 in Coevolution of HIV-1 with T Cells Leading to Poorer Clinical Outcomes

Differential haplotype expression in class I MHC genes during SARS-CoV-2 infection of human lung cell lines

Differential haplotype expression in class I MHC genes during SARS-CoV-2 infection of human lung cell lines

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Product

Resources

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Collaboration of a Detrimental HLA-B35:01 Allele with HLA-A24:02 in Coevolution of HIV-1 with T Cells Leading to Poorer Clinical Outcomes

Collaboration of a Detrimental HLA-B35:01 Allele with HLA-A24:02 in Coevolution of HIV-1 with T Cells Leading to Poorer Clinical Outcomes