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
Affiliations
Hannah S. Sperber
Vitalant Research Institute, San Francisco, CA, USA; Free University of Berlin, Institute of Biochemistry, Berlin, Germany; University of California, San Francisco, San Francisco, CA, USA; University Hospital Essen, Institute for Translational HIV Research, Essen, Germany
Kyle A. Raymond
Vitalant Research Institute, San Francisco, CA, USA; University of California, San Francisco, San Francisco, CA, USA
Mohamed S. Bouzidi
Vitalant Research Institute, San Francisco, CA, USA; University of California, San Francisco, San Francisco, CA, USA
Tongcui Ma
University of California, San Francisco, San Francisco, CA, USA; Gladstone Institutes, San Francisco, CA, USA
Silvana Valdebenito
The University of Texas Medical Branch, Galveston, TX, USA
Eliseo A. Eugenin
The University of Texas Medical Branch, Galveston, TX, USA
Nadia R. Roan
University of California, San Francisco, San Francisco, CA, USA; Gladstone Institutes, San Francisco, CA, USA
Steven G. Deeks
University of California, San Francisco, San Francisco, CA, USA
Sandra Winning
University of Duisburg-Essen, Institute for Physiology, Essen, Germany
Joachim Fandrey
University of Duisburg-Essen, Institute for Physiology, Essen, Germany
Roland Schwarzer
University Hospital Essen, Institute for Translational HIV Research, Essen, Germany; Corresponding author
Satish K. Pillai
Vitalant Research Institute, San Francisco, CA, USA; University of California, San Francisco, San Francisco, CA, USA; Corresponding author
Summary: 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.
