Phenotypic signatures of immune selection in HIV-1 reservoir cells

Weiwei Sun, Ce Gao, Ciputra Adijaya Hartana, Matthew R. Osborn, Kevin B. Einkauf, Xiaodong Lian, Benjamin Bone, Nathalie Bonheur, Tae-Wook Chun, Eric S. Rosenberg, Bruce D. Walker, Xu G. Yu and Mathias Lichterfeld ()
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Weiwei Sun: Ragon Institute of MGH, MIT and Harvard
Ce Gao: Ragon Institute of MGH, MIT and Harvard
Ciputra Adijaya Hartana: Ragon Institute of MGH, MIT and Harvard
Matthew R. Osborn: Ragon Institute of MGH, MIT and Harvard
Kevin B. Einkauf: Ragon Institute of MGH, MIT and Harvard
Xiaodong Lian: Ragon Institute of MGH, MIT and Harvard
Benjamin Bone: Ragon Institute of MGH, MIT and Harvard
Nathalie Bonheur: Ragon Institute of MGH, MIT and Harvard
Tae-Wook Chun: National Institute of Allergies and Infectious Diseases
Eric S. Rosenberg: Infectious Disease Division, Massachusetts General Hospital
Bruce D. Walker: Ragon Institute of MGH, MIT and Harvard
Xu G. Yu: Ragon Institute of MGH, MIT and Harvard
Mathias Lichterfeld: Ragon Institute of MGH, MIT and Harvard

Nature, 2023, vol. 614, issue 7947, 309-317

Abstract: Abstract Human immunodeficiency virus 1 (HIV-1) reservoir cells persist lifelong despite antiretroviral treatment1,2 but may be vulnerable to host immune responses that could be exploited in strategies to cure HIV-1. Here we used a single-cell, next-generation sequencing approach for the direct ex vivo phenotypic profiling of individual HIV-1-infected memory CD4+ T cells from peripheral blood and lymph nodes of people living with HIV-1 and receiving antiretroviral treatment for approximately 10 years. We demonstrate that in peripheral blood, cells harbouring genome-intact proviruses and large clones of virally infected cells frequently express ensemble signatures of surface markers conferring increased resistance to immune-mediated killing by cytotoxic T and natural killer cells, paired with elevated levels of expression of immune checkpoint markers likely to limit proviral gene transcription; this phenotypic profile might reduce HIV-1 reservoir cell exposure to and killing by cellular host immune responses. Viral reservoir cells harbouring intact HIV-1 from lymph nodes exhibited a phenotypic signature primarily characterized by upregulation of surface markers promoting cell survival, including CD44, CD28, CD127 and the IL-21 receptor. Together, these results suggest compartmentalized phenotypic signatures of immune selection in HIV-1 reservoir cells, implying that only small subsets of infected cells with optimal adaptation to their anatomical immune microenvironment are able to survive during long-term antiretroviral treatment. The identification of phenotypic markers distinguishing viral reservoir cells may inform future approaches for strategies to cure and eradicate HIV-1.

Date: 2023
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DOI: 10.1038/s41586-022-05538-8

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