Background: Although it is established that CD8+ T-cell immunity is critical for the control of HIV replication in vivo, the key factors that determine antiviral efficacy are yet to be fully elucidated. Antigen-sensitivity and T-cell receptor (TCR) avidity have been identified as potential determinants of CD8+ T-cell efficacy. However, there is no general consensus in this regard because the relationship between these parameters and the control of HIV infection has been established primarily in the context of immunodominant CD8+ T-cell responses against the Gag263–272 KK10 epitope restricted by human leukocyte antigen (HLA)-B27.
Methods: To investigate the relationship between antigen-sensitivity, TCR avidity and HIV-suppressive capacity in vitro across epitope specificities and HLA class I restriction elements, we used a variety of techniques to study CD8+ T-cell clones specific for Nef73–82 QK10 and Gag20–29 RY10, both restricted by HLA-A3, alongside CD8+ T-cell clones specific for Gag263–272 KK10.
Results: For each targeted epitope, the linked parameters of antigen-sensitivity and TCR avidity correlated directly with antiviral efficacy. However, marked differences in HIV-suppressive capacity were observed between epitope specificities, HLA class I restriction elements and viral isolates.
Conclusions: Collectively, these data emphasize the central role of the TCR as a determinant of CD8+ T-cell efficacy and demonstrate that the complexities of antigen recognition across epitope and HLA class I boundaries can confound simple relationships between TCR engagement and HIV suppression.
aINSERM UMR S 945, Infections and Immunity, Université Pierre et Marie Curie-Paris6, Hôpital Pitié-Salpêtrière, Paris, France
bInstitute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, Wales, UK
cInstitut Pasteur, Unité de Régulation des Infections Rétrovirales, Paris, France.
*Anna Lissina and Solène Fastenackels contributed equally to this writing of this work.
†Current address: Centro de Investigacion en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico.
Correspondence to Victor Appay, INSERM UMR S 945, Infections and Immunity, Avenir Group, Université Pierre et Marie Curie-Paris6, Hôpital Pitié-Salpêtrière, Paris, France. Tel: +33 1 40 77 81 83; fax: +33 1 40 77 97 34; e-mail: firstname.lastname@example.org
Received 11 July, 2013
Revised 3 December, 2013
Accepted 3 December, 2013