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IL-15 regulates susceptibility of CD4+ T cells to HIV infection

L. Manganaro,P. Hong,M. Hernandez,Dionne Argyle,L. Mulder,U. Potla,F. Diaz-Griffero,Benhur Lee,A. Fernández-Sesma,V. Simon

Published 2018 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance HIV creates a persistent reservoir, which is largely resistant to current antiretroviral treatment aimed at inhibiting HIV replication. CD4+ T memory lymphocytes, key components of this reservoir, are generally refractory to infection, but stimulation with γc-chain cytokines, such as IL-15, renders these cells more susceptible to HIV. We found that, by inducing cell cycle entry of CD4+ T cells, JAK1 is a key mediator responsible for counteracting the antiviral activity of SAM domain and HD domain-containing protein 1 (SAMHD1). Pharmacological inhibition of these kinases resulted in restoration of SAMHD1 in CD4+ T cells. Protecting these cells during the critical IL-15 surge observed during primary infection has the potential to limit reservoir establishment. HIV integrates into the host genome to create a persistent viral reservoir. Stimulation of CD4+ memory T lymphocytes with common γc-chain cytokines renders these cells more susceptible to HIV infection, making them a key component of the reservoir itself. IL-15 is up-regulated during primary HIV infection, a time when the HIV reservoir established. Therefore, we investigated the molecular and cellular impact of IL-15 on CD4+ T-cell infection. We found that IL-15 stimulation induces SAM domain and HD domain-containing protein 1 (SAMHD1) phosphorylation due to cell cycle entry, relieving an early block to infection. Perturbation of the pathways downstream of IL-15 receptor (IL-15R) indicated that SAMHD1 phosphorylation after IL-15 stimulation is JAK dependent. Treating CD4+ T cells with Ruxolitinib, an inhibitor of JAK1 and JAK2, effectively blocked IL-15–induced SAMHD1 phosphorylation and protected CD4+ T cells from HIV infection. Using high-resolution single-cell immune profiling using mass cytometry by TOF (CyTOF), we found that IL-15 stimulation altered the composition of CD4+ T-cell memory populations by increasing proliferation of memory CD4+ T cells, including CD4+ T memory stem cells (TSCM). IL-15–stimulated CD4+ TSCM, harboring phosphorylated SAMHD1, were preferentially infected. We propose that IL-15 plays a pivotal role in creating a self-renewing, persistent HIV reservoir by facilitating infection of CD4+ T cells with stem cell-like properties. Time-limited interventions with JAK1 inhibitors, such as Ruxolitinib, should prevent the inactivation of the endogenous restriction factor SAMHD1 and protect this long-lived CD4+ T-memory cell population from HIV infection.

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