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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / pathology
  • CD4-Positive T-Lymphocytes / virology
  • Disease Susceptibility
  • Female
  • HEK293 Cells
  • HIV Infections / immunology*
  • HIV Infections / pathology
  • HIV-1 / immunology*
  • Humans
  • Interleukin-15 / immunology*
  • Janus Kinase 1 / immunology
  • Janus Kinase 2 / immunology
  • Male
  • Memory, Short-Term
  • Nitriles
  • Pyrazoles / pharmacology
  • Pyrimidines
  • SAM Domain and HD Domain-Containing Protein 1 / immunology

Substances

  • IL15 protein, human
  • Interleukin-15
  • Nitriles
  • Pyrazoles
  • Pyrimidines
  • ruxolitinib
  • JAK1 protein, human
  • JAK2 protein, human
  • Janus Kinase 1
  • Janus Kinase 2
  • SAM Domain and HD Domain-Containing Protein 1
  • SAMHD1 protein, human