HLA-E–restricted HIV-1–specific CD8+ T cell responses in natural infection
Anju Bansal, … , June Kan-Mitchell, Paul A. Goepfert
Anju Bansal, … , June Kan-Mitchell, Paul A. Goepfert
Published July 6, 2021
Citation Information: J Clin Invest. 2021;131(16):e148979. https://doi.org/10.1172/JCI148979.
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Research Article Infectious disease

HLA-E–restricted HIV-1–specific CD8+ T cell responses in natural infection

Abstract

CD8+ T cell responses restricted by MHC-E, a nonclassical MHC molecule, have been associated with protection in an SIV/rhesus macaque model. The biological relevance of HLA-E–restricted CD8+ T cell responses in HIV infection, however, remains unknown. In this study, CD8+ T cells responding to HIV-1 Gag peptides presented by HLA-E were analyzed. Using in vitro assays, we observed HLA-E–restricted T cell responses to what we believe to be a newly identified subdominant Gag-KL9 as well as a well-described immunodominant Gag-KF11 epitope in T cell lines derived from chronically HIV-infected patients and also primed from healthy donors. Blocking of the HLA-E/KF11 binding by the B7 signal peptide resulted in decreased CD8+ T cell responses. KF11 presented via HLA-E in HIV-infected cells was recognized by antigen-specific CD8+ T cells. Importantly, bulk CD8+ T cells obtained from HIV-infected individuals recognized infected cells via HLA-E presentation. Ex vivo analyses at the epitope level showed a higher responder frequency of HLA-E–restricted responses to KF11 compared with KL9. Taken together, our findings of HLA-E–restricted HIV-specific immune responses offer intriguing and possibly paradigm-shifting insights into factors that contribute to the immunodominance of CD8+ T cell responses in HIV infection.

Authors

Anju Bansal, Mika N. Gehre, Kai Qin, Sarah Sterrett, Ayub Ali, Ying Dang, Sojan Abraham, Margaret C. Costanzo, Leon A. Venegas, Jianming Tang, N. Manjunath, Mark A. Brockman, Otto O. Yang, June Kan-Mitchell, Paul A. Goepfert

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Figure 3

Activation of KF11-specific CD8+ T cells by HIV-1–infected target cells expressing HLA-E and CD4.

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Activation of KF11-specific CD8+ T cells by HIV-1–infected target cells ...
(A) Confirmation of surface expression of CD4 by 221ΔE.CD4, 221ΔE.E*01.CD4, 221ΔE.E*03.CD4, and 221ΔE.B*57.CD4 cell lines. Staining by isotype-matched negative control mAbs is also depicted in each case. (B) Percentages of p24+ cells and increasing intensity of cytoplasmic p24 staining (mAb Kc57) in a representative NL4-3–infected cell line (221ΔE.CD4) over 96 hours. (C) Degranulation of CD94–CD8hi T cells from patients CHI-4 and CHI-24 after incubation with NL4-3–infected 221ΔE.CD4, 221ΔE.E*01.CD4, 221ΔE.E*03.CD4, or 221ΔE.B*57.CD4 target cells. Effector cells were generated by in vitro stimulation with 10 μg/mL KF11 peptide. Target cells were assessed 48 hours after infection with 18% of the cells staining for p24. KF11-pulsed target cells were included as positive controls, while 221ΔE.CD4 cells (KF11-pulsed or NL4-3–infected) served as negative controls.