title: Disease progression despite protective HLA expression in an HIV-infected transmission pair.
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.
authors.affiliation: Department of Paediatrics, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, OX1 3SY, UK. jacqui.brener@wolfson.ox.ac.uk.
authors.forename: Jacqui
authors.initials: J
authors.lastname: Brener
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK. ag8@sanger.ac.uk.
authors.forename: Astrid
authors.initials: A
authors.lastname: Gall
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Boston, MA, USA. rbatorsky@mgh.harvard.edu.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Batorsky
authors.affiliation: Integrated Sexual Health Services, Northamptonshire Healthcare NHS Foundation Trust, Northampton General Hospital, Cliftonville, Northampton, NN1 5BD, UK. joanne.whitcombe@nhft.nhs.uk.
authors.forename: Lynn
authors.initials: L
authors.lastname: Riddell
authors.affiliation: Department of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen N, Denmark. sbuus@sund.ku.dk.
authors.forename: Soren
authors.initials: S
authors.lastname: Buus
authors.affiliation: Department of Paediatrics, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, OX1 3SY, UK. ellen.leitman@st-hughs.ox.ac.uk.
authors.forename: Ellen
authors.initials: E
authors.lastname: Leitman
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK. pk5@sanger.ac.uk.|Division of Infection and Immunity, University College London, Gower Street, London, WC1E 6BT, UK. pk5@sanger.ac.uk.
authors.forename: Paul
authors.initials: P
authors.lastname: Kellam
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Boston, MA, USA. TALLEN2@mgh.harvard.edu.
authors.forename: Todd
authors.initials: T
authors.lastname: Allen
authors.affiliation: Department of Paediatrics, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, OX1 3SY, UK. philip.goulder@paediatrics.ox.ac.uk.
authors.forename: Philip
authors.initials: P
authors.lastname: Goulder
authors.affiliation: Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, OX1 3SY, UK. p.matthews@doctors.org.uk.
authors.forename: Philippa C
authors.initials: PC
authors.lastname: Matthews
mesh_terms: D000328:Adult; D018450:Disease Progression; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005191:Family Characteristics; D005260:Female; D015870:Gene Expression; D006678:HIV / Q000145:classification / Q000235:genetics; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology* / Q000635:transmission; D015235:HLA-B Antigens / Q000378:metabolism*; D015796:HLA-B27 Antigen / Q000378:metabolism*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D017422:Sequence Analysis, DNA; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology
chemical_list: D000939:Epitopes; D015235:HLA-B Antigens; C464936:HLA-B*27:05 antigen; C484830:HLA-B*57:01 antigen; D015796:HLA-B27 Antigen; D054301:gag Gene Products, Human Immunodeficiency Virus