The hypoxia-regulated ectonucleotidase CD73 is a host determinant of HIV latency

Hannah S. Sperber, Kyle A. Raymond, Mohamed S. Bouzidi, Tongcui Ma, Silvana Valdebenito, Eliseo A. Eugenin, Nadia R. Roan, Steven G. Deeks, Sandra Winning, Joachim Fandrey, Roland Schwarzer, Satish K. Pillai

    Research output: Contribution to journalArticlepeer-review

    4 Scopus citations

    Abstract

    Deciphering the mechanisms underlying viral persistence is critical to achieving a cure for human immunodeficiency virus (HIV) infection. Here, we implement a systems approach to discover molecular signatures of HIV latently infected CD4+ T cells, identifying the immunosuppressive, adenosine-producing ectonucleotidase CD73 as a key surface marker of latent cells. Hypoxic conditioning, reflecting the lymphoid tissue microenvironment, increases the frequency of CD73+ CD4+ T cells and promotes HIV latency. Transcriptomic profiles of CD73+ CD4+ T cells favor viral quiescence, immune evasion, and cell survival. CD73+ CD4+ T cells are capable of harboring a functional HIV reservoir and reinitiating productive infection ex vivo. CD73 or adenosine receptor blockade facilitates latent HIV reactivation in vitro, mechanistically linking adenosine signaling to viral quiescence. Finally, tissue imaging of lymph nodes from HIV-infected individuals on antiretroviral therapy reveals spatial association between CD73 expression and HIV persistence in vivo. Our findings warrant development of HIV-cure strategies targeting the hypoxia-CD73-adenosine axis.

    Original languageEnglish (US)
    Article number113285
    JournalCell Reports
    Volume42
    Issue number11
    DOIs
    StatePublished - Nov 28 2023

    Keywords

    • CD39
    • CD73
    • CP: Immunology
    • CP: Microbiology
    • HIV cure
    • IL-8
    • adenosine
    • eradication
    • hypoxia
    • lymphoid tissues
    • persistence
    • reservoir

    ASJC Scopus subject areas

    • General Biochemistry, Genetics and Molecular Biology

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