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


ABSTRACT: HIV integrates into the host genome to create a persistent viral reservoir. Stimulation of CD4+ memory T lymphocytes with common ?c-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.

SUBMITTER: Manganaro L 

PROVIDER: S-EPMC6187195 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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IL-15 regulates susceptibility of CD4<sup>+</sup> T cells to HIV infection.

Manganaro Lara L   Hong Patrick P   Hernandez Matthew M MM   Argyle Dionne D   Mulder Lubbertus C F LCF   Potla Uma U   Diaz-Griffero Felipe F   Lee Benhur B   Fernandez-Sesma Ana A   Simon Viviana V  

Proceedings of the National Academy of Sciences of the United States of America 20180926 41


HIV integrates into the host genome to create a persistent viral reservoir. Stimulation of CD4<sup>+</sup> 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<sup>+</sup> T-cell infection. We found that IL-15 stimulation  ...[more]

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