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 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.

Expansion of Stem Cell-Like CD4+Memory T Cells during Acute HIV-1 Infection Is Linked to Rapid Disease Progression

“…However, it is unclear whether these CD95 ϩ CD4 ϩ T cells already encountered cognate antigen and can therefore be considered true antigen-experienced memory cells. This is also true for most of publications investigating SCM during HIV-1/SIV-1 infection using similar methods and will warrant further investigations (16,23,32,33).…”

HIV protease cleaves the antiviral m6A reader protein YTHDF3 in the viral particle

“…Cells were infected with VSV-G-pseudotyped single-cycle NL4-3ΔEnv viruses in triplicates for 5 hours, upon which cells were washed with PBS and culture media was replenished. HIV-1 early RT products [19], HIV late RT products [45,46], and unspliced GAPDH [9] were measured at 5, 23, 29, and 53 hours post infection by SYBR green qPCR (Roche). Early RT and late RT product levels were quantified in duplicates relative to unspliced GAPDH levels using the delta cycle threshold (CT) method.…”

CD4+T cell activation and associated susceptibility to HIV‐1 infection in vitro increased following acute resistance exercise in human subjects

“…Here, we propose to use HIV-1 infection as a biological model to independently asses CD4 + T cell activation state. Notably, quiescent CD4 + T cells, which are metabolically and transcriptionally silent (Yusuf and Fruman 2003;Tzachanis et al 2004), were originally thought to be refractory to HIV infection; however, evidence suggests that partially activated cells can support infection, especially with subsequent stimulation (Stevenson et al 1990;Zack et al 1990Zack et al , 1992Korin and Zack, 1998;Unutmaz et al 1999;Manganaro et al 2018).…”