The Hypoxia-regulated Ectonucleotidase CD73 is a Host Determinant of HIV Latency

Deciphering the mechanisms underlying viral persistence is critical to achieving a cure for HIV infection. We uncovered molecular signatures of HIV latently-infected CD4+ T cells, identifying the adenosine-producing ectonucleotidase CD73 as a key marker of latent infection. Hypoxic conditioning, reflective of tissue microenvironments, increased the frequency of CD73+ CD4+ T cells and promoted HIV latency. Transcriptomic profiles of CD73+ CD4+ T cells indicated expression phenotypes favoring viral persistence, immune evasion, and cell survival. Further, we demonstrate that CD73+ CD4+ T cells harbor a functional HIV reservoir and are capable of reinitiating productive infection in vitro. Moreover, blocking of the A2A receptor facilitates HIV reactivation in vitro, linking adenosine signaling to viral quiescence. Finally, tissue imaging of lymph nodes from HIV-infected individuals on antiretroviral therapy reveal spatial association between CD73 expression and HIV persistence in vivo. Our findings warrant exploration of the hypoxia-CD73-adenosine axis in curative strategies to promote viral eradication.