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Disease progression despite protective HLA expression in an HIV-infected transmission pair.

Brener J, Gall A, Batorsky R, Riddell L, Buus S, Leitman E, Kellam P, Allen T, Goulder P, Matthews PC - Retrovirology (2015)

Bottom Line: Using a heat map method to highlight differences in the viral sequences between donor and recipient, we demonstrated that the majority of the recipient's mutations outside of Env were within epitopes restricted by HLA-B*27:05 and HLA-B*57:01, including the well-studied Gag epitopes.The donor, who also expressed HLA alleles associated with disease protection, HLA-A*32:01/B*13:02/B*14:01, showed selection of mutations in parallel with disease progression within epitopes restricted by these protective alleles.The transmission of subtype CRF01_AE clade infection may have contributed to accelerated disease progression in this pair as a result of clade-specific sequence differences in immunodominant epitopes.

View Article: PubMed Central - PubMed

Affiliation: Department of Paediatrics, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, OX1 3SY, UK. jacqui.brener@wolfson.ox.ac.uk.

ABSTRACT

Background: The precise immune responses mediated by HLA class I molecules such as HLA-B*27:05 and HLA-B*57:01 that protect against HIV disease progression remain unclear. We studied a CRF01_AE clade HIV infected donor-recipient transmission pair in which the recipient expressed both HLA-B*27:05 and HLA-B*57:01.

Results: Within 4.5 years of diagnosis, the recipient had progressed to meet criteria for antiretroviral therapy initiation. We employed ultra-deep sequencing of the full-length virus genome in both donor and recipient as an unbiased approach by which to identify specific viral mutations selected in association with progression. Using a heat map method to highlight differences in the viral sequences between donor and recipient, we demonstrated that the majority of the recipient's mutations outside of Env were within epitopes restricted by HLA-B*27:05 and HLA-B*57:01, including the well-studied Gag epitopes. The donor, who also expressed HLA alleles associated with disease protection, HLA-A*32:01/B*13:02/B*14:01, showed selection of mutations in parallel with disease progression within epitopes restricted by these protective alleles.

Conclusions: These studies of full-length viral sequences in a transmission pair, both of whom expressed protective HLA alleles but nevertheless failed to control viremia, are consistent with previous reports pointing to the critical role of Gag-specific CD8+ T cell responses restricted by protective HLA molecules in maintaining immune control of HIV infection. The transmission of subtype CRF01_AE clade infection may have contributed to accelerated disease progression in this pair as a result of clade-specific sequence differences in immunodominant epitopes.

No MeSH data available.


Related in: MedlinePlus

Comparison of inter- and intra-host diversity of HIV quasispecies in a transmission pair. a Heat map representation of inter-host amino acid diversity across the full-length HIV genome, comparing donor and recipient. For the baseline, we used the donor sequence at 8 months post-diagnosis (which in this case represents the closest approximation of the founder virus); variation in the recipient at 52 months post-diagnosis is compared to this baseline. Each square represents a single codon, coloured to reflect the percentage of sequences in the recipient that differ from the consensus residue in the donor. b Heat map representation of intra-host amino acid diversity in the recipient at 52 months post-diagnosis. For the baseline, we used the recipient consensus sequence at 52 months post-diagnosis to which the intra-host recipient population at the same timepoint is compared. Each square represents a single codon coloured to reflect the percentage of minor variants in the recipient that differ from the consensus (‘baseline’) residue. c Percentage of true amino acid mismatches (excluding positions where the recipient’s sequence was represented as a minor variant in the donor) between donor and recipient sequences by gene. The proportion of mismatches at sites where there is a known or predicted association with the recipient’s HLA alleles is indicated. d Percentage of diverse amino acid sites (variability >10%) in the recipient intra-host population by gene. The proportion of diverse sites where there is a known or predicted association with the recipient’s HLA alleles is indicated.
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Fig6: Comparison of inter- and intra-host diversity of HIV quasispecies in a transmission pair. a Heat map representation of inter-host amino acid diversity across the full-length HIV genome, comparing donor and recipient. For the baseline, we used the donor sequence at 8 months post-diagnosis (which in this case represents the closest approximation of the founder virus); variation in the recipient at 52 months post-diagnosis is compared to this baseline. Each square represents a single codon, coloured to reflect the percentage of sequences in the recipient that differ from the consensus residue in the donor. b Heat map representation of intra-host amino acid diversity in the recipient at 52 months post-diagnosis. For the baseline, we used the recipient consensus sequence at 52 months post-diagnosis to which the intra-host recipient population at the same timepoint is compared. Each square represents a single codon coloured to reflect the percentage of minor variants in the recipient that differ from the consensus (‘baseline’) residue. c Percentage of true amino acid mismatches (excluding positions where the recipient’s sequence was represented as a minor variant in the donor) between donor and recipient sequences by gene. The proportion of mismatches at sites where there is a known or predicted association with the recipient’s HLA alleles is indicated. d Percentage of diverse amino acid sites (variability >10%) in the recipient intra-host population by gene. The proportion of diverse sites where there is a known or predicted association with the recipient’s HLA alleles is indicated.

Mentions: To investigate whether other sequence changes outside of the well-studied region of p24 Gag might also have contributed to progression in the HLA-B*27:05/57:01-positive recipient, we next examined the ultra-deep sequence data of the full-length HIV genome. Heat maps were generated in order to visualize the proportion of amino acid variants at each position compared to a given baseline. We identified all sites of complete amino acid mismatch between the donor and recipient that reflect inter-host evolution using the donor consensus sequence at 8 months as the baseline for comparison to the recipient (Figure 6a). We also identified sites of amino acid diversity in the recipient at 52 months, demonstrating intra-host evolution, using the recipient consensus sequence at the same timepoint as the baseline for comparison (Figure 6b). The heat map analyses that were generated highlight the location of residues changing most rapidly in the recipient and which arose within CD8+ T cell epitopes (Figures 6, 7).Figure 6


Disease progression despite protective HLA expression in an HIV-infected transmission pair.

Brener J, Gall A, Batorsky R, Riddell L, Buus S, Leitman E, Kellam P, Allen T, Goulder P, Matthews PC - Retrovirology (2015)

Comparison of inter- and intra-host diversity of HIV quasispecies in a transmission pair. a Heat map representation of inter-host amino acid diversity across the full-length HIV genome, comparing donor and recipient. For the baseline, we used the donor sequence at 8 months post-diagnosis (which in this case represents the closest approximation of the founder virus); variation in the recipient at 52 months post-diagnosis is compared to this baseline. Each square represents a single codon, coloured to reflect the percentage of sequences in the recipient that differ from the consensus residue in the donor. b Heat map representation of intra-host amino acid diversity in the recipient at 52 months post-diagnosis. For the baseline, we used the recipient consensus sequence at 52 months post-diagnosis to which the intra-host recipient population at the same timepoint is compared. Each square represents a single codon coloured to reflect the percentage of minor variants in the recipient that differ from the consensus (‘baseline’) residue. c Percentage of true amino acid mismatches (excluding positions where the recipient’s sequence was represented as a minor variant in the donor) between donor and recipient sequences by gene. The proportion of mismatches at sites where there is a known or predicted association with the recipient’s HLA alleles is indicated. d Percentage of diverse amino acid sites (variability >10%) in the recipient intra-host population by gene. The proportion of diverse sites where there is a known or predicted association with the recipient’s HLA alleles is indicated.
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Fig6: Comparison of inter- and intra-host diversity of HIV quasispecies in a transmission pair. a Heat map representation of inter-host amino acid diversity across the full-length HIV genome, comparing donor and recipient. For the baseline, we used the donor sequence at 8 months post-diagnosis (which in this case represents the closest approximation of the founder virus); variation in the recipient at 52 months post-diagnosis is compared to this baseline. Each square represents a single codon, coloured to reflect the percentage of sequences in the recipient that differ from the consensus residue in the donor. b Heat map representation of intra-host amino acid diversity in the recipient at 52 months post-diagnosis. For the baseline, we used the recipient consensus sequence at 52 months post-diagnosis to which the intra-host recipient population at the same timepoint is compared. Each square represents a single codon coloured to reflect the percentage of minor variants in the recipient that differ from the consensus (‘baseline’) residue. c Percentage of true amino acid mismatches (excluding positions where the recipient’s sequence was represented as a minor variant in the donor) between donor and recipient sequences by gene. The proportion of mismatches at sites where there is a known or predicted association with the recipient’s HLA alleles is indicated. d Percentage of diverse amino acid sites (variability >10%) in the recipient intra-host population by gene. The proportion of diverse sites where there is a known or predicted association with the recipient’s HLA alleles is indicated.
Mentions: To investigate whether other sequence changes outside of the well-studied region of p24 Gag might also have contributed to progression in the HLA-B*27:05/57:01-positive recipient, we next examined the ultra-deep sequence data of the full-length HIV genome. Heat maps were generated in order to visualize the proportion of amino acid variants at each position compared to a given baseline. We identified all sites of complete amino acid mismatch between the donor and recipient that reflect inter-host evolution using the donor consensus sequence at 8 months as the baseline for comparison to the recipient (Figure 6a). We also identified sites of amino acid diversity in the recipient at 52 months, demonstrating intra-host evolution, using the recipient consensus sequence at the same timepoint as the baseline for comparison (Figure 6b). The heat map analyses that were generated highlight the location of residues changing most rapidly in the recipient and which arose within CD8+ T cell epitopes (Figures 6, 7).Figure 6

Bottom Line: Using a heat map method to highlight differences in the viral sequences between donor and recipient, we demonstrated that the majority of the recipient's mutations outside of Env were within epitopes restricted by HLA-B*27:05 and HLA-B*57:01, including the well-studied Gag epitopes.The donor, who also expressed HLA alleles associated with disease protection, HLA-A*32:01/B*13:02/B*14:01, showed selection of mutations in parallel with disease progression within epitopes restricted by these protective alleles.The transmission of subtype CRF01_AE clade infection may have contributed to accelerated disease progression in this pair as a result of clade-specific sequence differences in immunodominant epitopes.

View Article: PubMed Central - PubMed

Affiliation: Department of Paediatrics, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, OX1 3SY, UK. jacqui.brener@wolfson.ox.ac.uk.

ABSTRACT

Background: The precise immune responses mediated by HLA class I molecules such as HLA-B*27:05 and HLA-B*57:01 that protect against HIV disease progression remain unclear. We studied a CRF01_AE clade HIV infected donor-recipient transmission pair in which the recipient expressed both HLA-B*27:05 and HLA-B*57:01.

Results: Within 4.5 years of diagnosis, the recipient had progressed to meet criteria for antiretroviral therapy initiation. We employed ultra-deep sequencing of the full-length virus genome in both donor and recipient as an unbiased approach by which to identify specific viral mutations selected in association with progression. Using a heat map method to highlight differences in the viral sequences between donor and recipient, we demonstrated that the majority of the recipient's mutations outside of Env were within epitopes restricted by HLA-B*27:05 and HLA-B*57:01, including the well-studied Gag epitopes. The donor, who also expressed HLA alleles associated with disease protection, HLA-A*32:01/B*13:02/B*14:01, showed selection of mutations in parallel with disease progression within epitopes restricted by these protective alleles.

Conclusions: These studies of full-length viral sequences in a transmission pair, both of whom expressed protective HLA alleles but nevertheless failed to control viremia, are consistent with previous reports pointing to the critical role of Gag-specific CD8+ T cell responses restricted by protective HLA molecules in maintaining immune control of HIV infection. The transmission of subtype CRF01_AE clade infection may have contributed to accelerated disease progression in this pair as a result of clade-specific sequence differences in immunodominant epitopes.

No MeSH data available.


Related in: MedlinePlus