Objectives: A superior capacity of controlling HIV has been attributed to CD8+ T cells directed against HIV-Gag compared to Nef, particularly in the context of some protective human leukocyte antigen (HLA) alleles. To further elucidate this protective effect, we compared the multifunctional and differentiation characteristics of CD8+ T cells specific for HIV-Gag and Nef in HLA-B57/5801-positive and negative nonprogressors.
Methods: A head-to-head comparison of CD8+ T cells specific for HIV-Gag and Nef frequencies, cytokine production and differentiation was conducted, in 11 HLA-B57/5801+ and 11 HLA-B57/5801− HIV-infected individuals selected from a cohort of 53 nonprogressors by using IFN-γ-ELISpot assay and flow cytometry analysis of intracellular cytokine production and differentiation profile. Correlations with HIV parameters were studied.
Results: Frequencies of Gag-specific but not of Nef-specific CD8+ T cells correlated with peripheral blood mononuclear cell (PBMC)-associated HIV-DNA. The HIV-Gag and Nef-specific CD8+ T cells did not differ for IL-2 production in either HLA-B57/5801+ or HLA-B57/5801− individuals. The IFN-γ-producing Gag-specific CD8+ T cells in HLA-B57/5801+ individuals significantly differed from their Nef-specific counterparts by displaying higher proportions of central memory CD45RA-CCR7+ cells positive for CD27. This differentiation pattern was not observed in HLA-B57/5801− individuals. Only these HLA-B57/5801-positive Gag-specific CD27+ central memory CD8+ T cells, but not their Nef-specific counterparts, negatively correlated with cell-associated HIV-DNA.
Conclusion: HLA-B57/5801 drives a preferential CD27+ differentiation of central memory CD8+ T cells directed against HIV-Gag but not Nef that may contribute to the ability of Gag-specific CD8+ T cells to better control HIV in HLA-B57/5801+ nonprogressors.
aLaboratoire d'Immunité et Infections, INSERM, UMR-S 945, France
bIFR113, Laboratoire d'Immunité et Infections, France
cINSERM U943, Épidémiologie, stratégies thérapeutiques et virologie cliniques dans l'infection à VIH, Hôpital Pitié-Salpêtrière, UPMC Univ Paris, France
dInter IFR-UPMC Flow Cytometry Platform, France
eAP-HP, Hôpital Pitié-Salpêtrière, Laboratoire d'Immunologie Cellulaire et Tissulaire, France
fLaboratoire de Virologie, Hôpital Necker, Université René Descartes, France
gUPMC Univ Paris 06, INSERM UMR-S 945, Laboratoire d'Immunité et Infections, Paris, France.
1J.X. and W.L. contributed equally to the writing of the article.
2The ALT-ANRS-CO15 study group is mentioned in Acknowledgements section.
Received 8 December, 2009
Revised 3 July, 2010
Accepted 14 July, 2010
Correspondence to Professor Brigitte Autran, INSERM UMR-S 945, Laboratoire d'Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, 83 Bld de l'Hôpital, 75013 Paris, France. E-mail: email@example.com