HLA-E–restricted HIV-1–specific CD8+ T cell responses in natural infection
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
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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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 6

Ex vivo–based bulk CD8+ T cell activation by HIV-1–infected target cells expressing HLA-E and CD4.

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Ex vivo–based bulk CD8+ T cell activation by HIV-1–infected target cells...
221ΔE cell lines expressing CD4 and either HLA-E*01:01, HLA-E*03:01, or HLA-B*57:01 were infected with NL4-3 virus (MOI = 0.5) for 12 hours, cultured for 48 hours, then cocultured with freshly isolated bulk CD8+ T cells from HIV-infected individuals (n = 7). CD8+ T cell production of IFN-γ alone or CD107a in combination with granzyme B, perforin, or IFN-γ was assessed after 12 hours of coculture with APCs. (A and B) HLA-E*01:01–, HLA-E*03:01–, and HLA-B*57:01–restricted CD8+ T cell responses from 2 representative individuals (patient 5 and patient 9; Supplemental Table 4). Red boxes indicate positive responses compared with uninfected controls. (C) Cumulative data from 7 individuals with both HLA-E*01:01– and HLA-B*57:01–restricted responses. Median values are shown, and error bars represent interquartile range. Data within groups were compared using Wilcoxon signed rank test.