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Virtual memory CD8+ T cells restrain the viral reservoir in HIV-1-infected patients with antiretroviral therapy through derepressing KIR-mediated inhibition

Cellular & Molecular Immunology volume 17, pages 1257–1265 (2020)Cite this article

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Abstract

The viral reservoir is the major hurdle in developing and establishing an HIV cure. Understanding factors affecting the size and decay of this reservoir is crucial for the development of therapeutic strategies. Recent work highlighted that CD8+ T cells are involved in the control of viral replication in ART-treated HIV-1-infected individuals, but how CD8+ T cells sense and restrict the HIV reservoir are not fully understood. Here, we demonstrate that a population of unconventional CD45RA+, PanKIR+, and/or NKG2A+ virtual memory CD8+ T cells (TVM cells), which confer rapid and robust protective immunity against pathogens, plays an important role in restraining the HIV DNA reservoir in HIV-1-infected patients with effective ART. In patients undergoing ART, TVM cells negatively correlate with HIV DNA and positively correlate with circulating IFN-α2 and IL-15. Moreover, TVM cells constitutively express high levels of cytotoxic granule components, including granzyme B, perforin and granulysin, and demonstrate the capability to control HIV replication through both cytolytic and noncytolytic mechanisms. Furthermore, by using an ex vivo system, we showed that HIV reactivation is effectively suppressed by TVM cells through KIR-mediated recognition. This study suggests that TVM cells are a promising target to predict posttreatment virological control and to design immune-based interventions to reduce the reservoir size in ART-treated HIV-1-infected individuals.

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Acknowledgements

We thank Chunbao Zhou and Jinhong Yuan (The Fifth Medical Center of the PLA General Hospital) for their technical support with flow cytometry analysis. This study was supported by the Innovation Groups of the National Natural Science Foundation of China (grant no. 81721002), the National Science and Technology Major Project (grant no. 2018ZX10302104-002) and National Natural Science Foundation of China (grant nos. 81901617 and 81772185).

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  1. These authors contributed equally: Jie-Hua Jin, Hui-Huang Huang

Authors and Affiliations

  1. Peking University 302 Clinical Medical School, Beijing, China

    Jie-Hua Jin, Ming Shi & Fu-Sheng Wang

  2. Treatment and Research Center for Infectious Diseases, The Fifth Medical Center of PLA General Hospital, Beijing, China

    Jie-Hua Jin, Hui-Huang Huang, Ming-Ju Zhou, Jing Li, Wei Hu, Lei Huang, Zhe Xu, Bo Tu, Guang Yang, Ming Shi, Yan-Mei Jiao, Xing Fan, Jin-Wen Song, Ji-Yuan Zhang, Chao Zhang & Fu-Sheng Wang

  3. National Clinical Research Center for Infectious Diseases, Beijing, China

    Jie-Hua Jin, Hui-Huang Huang, Ming-Ju Zhou, Jing Li, Wei Hu, Lei Huang, Zhe Xu, Bo Tu, Guang Yang, Ming Shi, Yan-Mei Jiao, Xing Fan, Jin-Wen Song, Ji-Yuan Zhang, Chao Zhang & Fu-Sheng Wang

  4. Bengbu Medical University, Bengbu, China

    Ming-Ju Zhou & Jing Li

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Contributions

F.W. and C.Z. conceived the study and wrote the paper with J.J. C.Z., J.J., and H.H. designed and performed most experiments and analyzed the data. The clinical samples and data were contributed by H.H., L.H., Z.X., and G.Y. M.Z., J.L., and W.H. performed flow cytometry on HIV samples. M.S., Y.J., X.F., and J.S. contributed to scientific planning. Intellectual input was provided by all authors.

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Correspondence to Chao Zhang or Fu-Sheng Wang.

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Jin, JH., Huang, HH., Zhou, MJ. et al. Virtual memory CD8+ T cells restrain the viral reservoir in HIV-1-infected patients with antiretroviral therapy through derepressing KIR-mediated inhibition. Cell Mol Immunol 17, 1257–1265 (2020). https://doi.org/10.1038/s41423-020-0408-9

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