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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: 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.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

Phylogenetic trees demonstrating subtype and genetic proximity of sequences from an HIV transmission pair. a Maximum likelihood phylogenetic tree of 92 6803 bp nucleotide sequences, including consensus sequences for clades A, B, C and CRF01_AE, donor sequences from 8, 20 and 42 months post-diagnosis and recipient sequences from 20, 42 and 52 months post-diagnosis and 82 CRF01_AE Clade sequences from Thailand (Los Alamos HIV database, http://www.hiv.lanl.gov/). Donor and recipient sequences (circled) cluster with CRF01_AE clade sequences from Thailand, confirming that the Thai epidemic is the likely source of infection. The bootstrap value based on 1,000 bootstrap replicates for the donor-recipient cluster is shown in italics. b The close relationship between donor and recipient sequences supports transmission between these two subjects. Bootstrap values >0.75 based on 1,000 bootstrap replicates are shown in italics. Scale bars show number of substitutions per site.
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Fig1: Phylogenetic trees demonstrating subtype and genetic proximity of sequences from an HIV transmission pair. a Maximum likelihood phylogenetic tree of 92 6803 bp nucleotide sequences, including consensus sequences for clades A, B, C and CRF01_AE, donor sequences from 8, 20 and 42 months post-diagnosis and recipient sequences from 20, 42 and 52 months post-diagnosis and 82 CRF01_AE Clade sequences from Thailand (Los Alamos HIV database, http://www.hiv.lanl.gov/). Donor and recipient sequences (circled) cluster with CRF01_AE clade sequences from Thailand, confirming that the Thai epidemic is the likely source of infection. The bootstrap value based on 1,000 bootstrap replicates for the donor-recipient cluster is shown in italics. b The close relationship between donor and recipient sequences supports transmission between these two subjects. Bootstrap values >0.75 based on 1,000 bootstrap replicates are shown in italics. Scale bars show number of substitutions per site.

Mentions: Using maximum likelihood analysis and Rega HIV-1 Subtyping Tool, we confirmed that the transmission pair was infected with CRF01_AE clade virus (Figure 1a and data not shown), the recombinant virus prevalent in Thailand [22, 23]. The close phylogenetic relationship of donor and recipient viruses suggests that these subjects are likely to be transmission partners (Figure 1b). As evidence to support the direction of transmission suggested by the clinical history, we found that an HLA-B*14:01 associated escape mutation, Gag-K302R (within the Gag-DA9 epitope [24]) present in the HLA-B*14:01-positive donor’s autologous virus, was transmitted to the HLA-B*14:01-negative recipient and subsequently reverted to wild-type in the recipient (Figure 2). In contrast, the HLA-B*27:05 and HLA-B*57:01-driven mutants observed in the recipient were not present in the donor.Figure 1


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)

Phylogenetic trees demonstrating subtype and genetic proximity of sequences from an HIV transmission pair. a Maximum likelihood phylogenetic tree of 92 6803 bp nucleotide sequences, including consensus sequences for clades A, B, C and CRF01_AE, donor sequences from 8, 20 and 42 months post-diagnosis and recipient sequences from 20, 42 and 52 months post-diagnosis and 82 CRF01_AE Clade sequences from Thailand (Los Alamos HIV database, http://www.hiv.lanl.gov/). Donor and recipient sequences (circled) cluster with CRF01_AE clade sequences from Thailand, confirming that the Thai epidemic is the likely source of infection. The bootstrap value based on 1,000 bootstrap replicates for the donor-recipient cluster is shown in italics. b The close relationship between donor and recipient sequences supports transmission between these two subjects. Bootstrap values >0.75 based on 1,000 bootstrap replicates are shown in italics. Scale bars show number of substitutions per site.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4487201&req=5

Fig1: Phylogenetic trees demonstrating subtype and genetic proximity of sequences from an HIV transmission pair. a Maximum likelihood phylogenetic tree of 92 6803 bp nucleotide sequences, including consensus sequences for clades A, B, C and CRF01_AE, donor sequences from 8, 20 and 42 months post-diagnosis and recipient sequences from 20, 42 and 52 months post-diagnosis and 82 CRF01_AE Clade sequences from Thailand (Los Alamos HIV database, http://www.hiv.lanl.gov/). Donor and recipient sequences (circled) cluster with CRF01_AE clade sequences from Thailand, confirming that the Thai epidemic is the likely source of infection. The bootstrap value based on 1,000 bootstrap replicates for the donor-recipient cluster is shown in italics. b The close relationship between donor and recipient sequences supports transmission between these two subjects. Bootstrap values >0.75 based on 1,000 bootstrap replicates are shown in italics. Scale bars show number of substitutions per site.
Mentions: Using maximum likelihood analysis and Rega HIV-1 Subtyping Tool, we confirmed that the transmission pair was infected with CRF01_AE clade virus (Figure 1a and data not shown), the recombinant virus prevalent in Thailand [22, 23]. The close phylogenetic relationship of donor and recipient viruses suggests that these subjects are likely to be transmission partners (Figure 1b). As evidence to support the direction of transmission suggested by the clinical history, we found that an HLA-B*14:01 associated escape mutation, Gag-K302R (within the Gag-DA9 epitope [24]) present in the HLA-B*14:01-positive donor’s autologous virus, was transmitted to the HLA-B*14:01-negative recipient and subsequently reverted to wild-type in the recipient (Figure 2). In contrast, the HLA-B*27:05 and HLA-B*57:01-driven mutants observed in the recipient were not present in the donor.Figure 1

Bottom Line: 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.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