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Proc Natl Acad Sci U S A. 2018 Oct 9;115(41):E9659-E9667. doi: 10.1073/pnas.1806695115. Epub 2018 Sep 26.

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

Author information

1
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029; manganaro@ingm.org viviana.simon@mssm.edu.
2
"Romeo ed Enrica Invernizzi," Istituto Nazionale di Genetica Molecolare (INGM), Milan 20122, Italy.
3
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
4
Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
5
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461.
6
Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.

Abstract

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.

KEYWORDS:

CD4 T memory stem cells; HIV; IL-15; SAMHD1

PMID:
30257946
PMCID:
PMC6187195
[Available on 2019-04-09]
DOI:
10.1073/pnas.1806695115
[Indexed for MEDLINE]

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