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IL-15 regulates susceptibility of CD4+ T cells to HIV infection.
- Source :
- Proceedings of the National Academy of Sciences of the United States of America; 10/9/2018, Vol. 115 Issue 41, pE9659-E9667, 9p
- Publication Year :
- 2018
-
Abstract
- HIV integrates into the host genome to create a persistent viral reservoir. Stimulation of CD4<superscript>+</superscript> 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<superscript>+</superscript> 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<superscript>+</superscript> T cells with Ruxolitinib, an inhibitor of JAK1 and JAK2, effectively blocked IL-15-induced SAMHD1 phosphorylation and protected CD4<superscript>+</superscript> 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<superscript>+</superscript> T-cell memory populations by increasing proliferation of memory CD4<superscript>+</superscript> T cells, including CD4<superscript>+</superscript> T memory stem cells (T<subscript>SCM</subscript>). IL-15-stimulated CD4<superscript>+</superscript> T<subscript>SCM</subscript>, 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<superscript>+</superscript> 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<superscript>+</superscript> T-memory cell population from HIV infection. [ABSTRACT FROM AUTHOR]
- Subjects :
- T cells
HIV infections
CD4 antigen
ANTIRETROVIRAL agents
MEDICAL microbiology
Subjects
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 115
- Issue :
- 41
- Database :
- Complementary Index
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 132312419
- Full Text :
- https://doi.org/10.1073/pnas.1806695115