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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

Alignment of HLA-B*27:05 and HLA-B*57:01-restricted epitopes in an HIV-1 transmission pair, showing sequences derived from donor and recipient, compared to consensus sequences for B clade and CRF01_AE clade. Known escape mutations in B clade infection are indicated in bold.
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Fig4: Alignment of HLA-B*27:05 and HLA-B*57:01-restricted epitopes in an HIV-1 transmission pair, showing sequences derived from donor and recipient, compared to consensus sequences for B clade and CRF01_AE clade. Known escape mutations in B clade infection are indicated in bold.

Mentions: We initially focused on the well-studied Gag epitopes restricted by HLA-B*27:05 and HLA-B*57:01, believed to play a central role in immune containment in subjects expressing these alleles [8, 26–28]. The presence in the AE clade consensus of the very residues that are selected in B or C clade infected subjects as escape mutants in two of the four HLA-27:05/B*57:01-restricted p24 Gag-specific epitopes, ISPRTLNAW (Gag 147-155, ‘ISW9’) and KAFSPEVIPMF (Gag 162-172, ‘KF11’), prompted the question of whether well-defined HLA-B*27:05/57:01-restricted epitopes are accessible in AE clade infection. Only six out of 20 HLA-B*27/B*57-restricted epitopes (HLA-B*57 Gag-TW10, Pol-IW9, Pol-KF9; HLA-B*27 Gag-IK9, Gag-KK10, Pol-KY9) previously shown to drive the selection of escape mutants [24], share the same consensus sequence in B and AE clades (Figure 4).Figure 4


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)

Alignment of HLA-B*27:05 and HLA-B*57:01-restricted epitopes in an HIV-1 transmission pair, showing sequences derived from donor and recipient, compared to consensus sequences for B clade and CRF01_AE clade. Known escape mutations in B clade infection are indicated in bold.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig4: Alignment of HLA-B*27:05 and HLA-B*57:01-restricted epitopes in an HIV-1 transmission pair, showing sequences derived from donor and recipient, compared to consensus sequences for B clade and CRF01_AE clade. Known escape mutations in B clade infection are indicated in bold.
Mentions: We initially focused on the well-studied Gag epitopes restricted by HLA-B*27:05 and HLA-B*57:01, believed to play a central role in immune containment in subjects expressing these alleles [8, 26–28]. The presence in the AE clade consensus of the very residues that are selected in B or C clade infected subjects as escape mutants in two of the four HLA-27:05/B*57:01-restricted p24 Gag-specific epitopes, ISPRTLNAW (Gag 147-155, ‘ISW9’) and KAFSPEVIPMF (Gag 162-172, ‘KF11’), prompted the question of whether well-defined HLA-B*27:05/57:01-restricted epitopes are accessible in AE clade infection. Only six out of 20 HLA-B*27/B*57-restricted epitopes (HLA-B*57 Gag-TW10, Pol-IW9, Pol-KF9; HLA-B*27 Gag-IK9, Gag-KK10, Pol-KY9) previously shown to drive the selection of escape mutants [24], share the same consensus sequence in B and AE clades (Figure 4).Figure 4

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