The Antiviral Efficacy of HIV-Specific CD8+ T-Cells to a Conserved Epitope Is Heavily Dependent on the Infecting HIV-1 Isolate

PLoS Pathogens

Geraldine M. Gillespie¹  Benedikt M. Kessler²  Holger B. Kramer²  Cynthia Wright²  Marie-Eve Blais³  Srinika R. F. Ranasinghe³  Alison Simmons³  Andrew J. McMichael³  Tao Dong³  Katalin di Gleria³  Yonghong Zhang³  Abigail Culshaw³  Sarah L. Rowland-Jones³  Tica Pichulik³ 

[1] BeiJing You'An Hospital, BeiJing Capital University, BeiJing, China;Henry Wellcome Building of Molecular Physiology, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom;Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom

关键词: Enzyme-linked immunoassays;    HIV-1;    Cloning;    T cells;    Vaccinia virus;    HIV;    Antigen processing;    recognition;    Recombinant vaccines;   

DOI  :  10.1371/journal.ppat.1001341

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

A major challenge to developing a successful HIV vaccine is the vast diversity of viral sequences, yet it is generally assumed that an epitope conserved between different strains will be recognised by responding T-cells. We examined whether an invariant HLA-B8 restricted Nef90–97 epitope FL8 shared between five high titre viruses and eight recombinant vaccinia viruses expressing Nef from different viral isolates (clades A–H) could activate antiviral activity in FL8-specific cytotoxic T-lymphocytes (CTL). Surprisingly, despite epitope conservation, we found that CTL antiviral efficacy is dependent on the infecting viral isolate. Only 23% of Nef proteins, expressed by HIV-1 isolates or as recombinant vaccinia-Nef, were optimally recognised by CTL. Recognition of the HIV-1 isolates by CTL was independent of clade-grouping but correlated with virus-specific polymorphisms in the epitope flanking region, which altered immunoproteasomal cleavage resulting in enhanced or impaired epitope generation. The finding that the majority of virus isolates failed to present this conserved epitope highlights the importance of viral variance in CTL epitope flanking regions on the efficiency of antigen processing, which has been considerably underestimated previously. This has important implications for future vaccine design strategies since efficient presentation of conserved viral epitopes is necessary to promote enhanced anti-viral immune responses.

【 授权许可】

CC BY