CD8 T cells cross-restricted by HLA-B*57 and HLA-E*01 recognize HIV Gag with different functional profiles

Kevin J. Maroney; Michael A. Rose; Allisa K. Oman; Abha Chopra; Hua-Shiuan Hsieh; Zerufael Derza; Rachel Waterworth; Mark A. Brockman; Spyros A. Kalams; Anju Bansal; Paul A. Goepfert

doi:10.1172/jci.insight.189909

CD8 T cells cross-restricted by HLA-B57 and HLA-E01 recognize HIV Gag with different functional profiles

Kevin J. Maroney,¹ Michael A. Rose,¹ Allisa K. Oman,¹ Abha Chopra,² Hua-Shiuan Hsieh,³ Zerufael Derza,³ Rachel Waterworth,³ Mark A. Brockman,³ Spyros A. Kalams,⁴ Anju Bansal,¹ and Paul A. Goepfert¹

Published December 18, 2025 - More info

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Abstract

Few HIV-specific epitopes restricted by non-classical HLA-E have been described, and even less is known about the functional profile of responding CD8 T cells (CD8s). This study evaluates the functional characteristics of CD8s targeting the Gag epitope KF11 (KAFSPEVIPMF) restricted by either HLA-E (E-CD8s) or HLA-B57 (B57-CD8s). CD8s from eight people with HIV (PWH) were cocultured with KF11 peptide presented by cell lines expressing HLA-B*57:01, HLA-E*01:01 or E*01:03. CD8 responses were analyzed using scRNA-seq and scTCR-seq. Supernatants were also assessed for soluble protein profiling. HLA-I multimers were developed to identify CD8s restricted by HLA-B57 and/or HLA-E ex vivo. B57-CD8s secreted higher levels of cytotoxic cytokines such as IFNγ, whereas E-CD8s produced more chemotactic cytokines, including RANTES, CXCL10 (IP-10), and IL27, findings which were corroborated through scRNA sequencing. TCR clonotypes stimulated by KF11 were cross-restricted by HLA-B*57 and HLA-E*01/03 as demonstrated by in vitro T cell reporter assays and ex vivo multimer screening. Ex vivo CD8s were singly restricted by HLA-B57 and HLA-E, with dual restriction only observed in PWH with lower viral load. These findings demonstrate that certain HIV-specific CD8s in PWH exhibit dual restriction by HLA-B*57 and HLA-E*01/03, leading to functionally distinct immune responses depending upon the restricting allele(s).

CD8 T cells cross-restricted by HLA-B57 and HLA-E01 recognize HIV Gag with different functional profiles

Kevin J. Maroney,¹ Michael A. Rose,¹ Allisa K. Oman,¹ Abha Chopra,² Hua-Shiuan Hsieh,³ Zerufael Derza,³ Rachel Waterworth,³ Mark A. Brockman,³ Spyros A. Kalams,⁴ Anju Bansal,¹ and Paul A. Goepfert¹

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CD8 T cells cross-restricted by HLA-B*57 and HLA-E*01 recognize HIV Gag with different functional profiles

Kevin J. Maroney,1 Michael A. Rose,1 Allisa K. Oman,1 Abha Chopra,2 Hua-Shiuan Hsieh,3 Zerufael Derza,3 Rachel Waterworth,3 Mark A. Brockman,3 Spyros A. Kalams,4 Anju Bansal,1 and Paul A. Goepfert1

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CD8 T cells cross-restricted by HLA-B57 and HLA-E01 recognize HIV Gag with different functional profiles

Kevin J. Maroney,¹ Michael A. Rose,¹ Allisa K. Oman,¹ Abha Chopra,² Hua-Shiuan Hsieh,³ Zerufael Derza,³ Rachel Waterworth,³ Mark A. Brockman,³ Spyros A. Kalams,⁴ Anju Bansal,¹ and Paul A. Goepfert¹