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

Retrovirology

Philippa C Matthews⁷  Philip Goulder⁴  Todd Allen⁶  Paul Kellam¹  Ellen Leitman⁴  Soren Buus²  Lynn Riddell⁵  Rebecca Batorsky⁶  Astrid Gall³  Jacqui Brener⁴ 

[1] Division of Infection and Immunity, University College London, Gower Street, London WC1E 6BT, UK;Department of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen N, Denmark;Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK;Department of Paediatrics, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford OX1 3SY, UK;Integrated Sexual Health Services, Northamptonshire Healthcare NHS Foundation Trust, Northampton General Hospital, Cliftonville, Northampton NN1 5BD, UK;Ragon Institute of MGH, MIT and Harvard, Boston, MA, USA;Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford OX1 3SY, UK

关键词: Ultra-deep sequencing;    Transmission pair;    CRF01_AE Clade;    CTL response;    HLA;    HIV-1;   

Others  :  1221137
DOI  :  10.1186/s12977-015-0179-z

 received in 2015-04-15, accepted in 2015-06-02,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Brener et al.

【 图 表 】

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