GSE210824
Activation of ISR/ATF4 signaling depletes HIV reservoir in CD4+ T cells
Latent HIV reservoirs are extremely stable which pose a tremendous challenge to eradicate HIV. Here, we show that HIV explores the integrated stress response (ISR) signaling to establish its quiescent infection, refractory to the clearance for its persistence. HA15, a recently characterized specific ISR agonist, activates ATF4/CHOP signaling to not only disrupt HIV latency but also reduce HIV+ cells in the primary CD4+ T cell model of HIV latency without the induction of cell death in the HIV negative primary CD4+ T cells and the impact of viability in resting CD4+ T cells isolated from people living with HIV (PLWH). Mechanistically, the reduction of HIV+ cells by ISR/ATF4 activation is associated with the enhancement of cellular apoptosis. However, this mainly occurs in the HIV translation negative CD4+ T cells. In fact, ISR/ATF4 activation-induced cell death largely occurs in HIV transcription active (HIV gag-pol) CD4+ T cells. This is involved in HIV RNA-induced innate immune IFIT signaling. During the acute SIV infection in the rhesus macaques, the induction of ATF4 is associated with decrease of SIV reservoir in the intestine in vivo. When further tested in the resting CD4+ T cells isolated from PLWH on ART, the induction of ISR/ATF4 signaling by HA15 reduced HIV DNA reservoir. These findings support that inactivation of ISR/ATF4 signaling is associated with the maintenance of the stable and quiescent HIV reservoirs while enforced ISR/ATF4 signaling reduces translation quiescent HIV reservoirs in CD4+ T cells. Overall design: Single-cell RNA-seq (10X 3' scRNA-seq) in control and HA15-treated primary CD4+ T cell model of HIV latency, in biological triplicate. Samples were run simultaneously via hashtag oligo (HTO).