The integrated stress response signaling during the persistent HIV infection.

Human immunodeficiency virus-1 (HIV) infection is a chronic disease under antiretroviral therapy (ART), during which active HIV replication is effectively suppressed. Stable viral reservoirs are established early in infection and cannot be eradicated in people with HIV (PWH) by ART alone, which features residual immune inflammation with disease-associated secondary comorbidities. Mammalian cells are equipped with integrated stress response (ISR) machinery to detect intrinsic and extrinsic stresses such as heme deficiency, nutrient fluctuation, the accumulation of unfolded proteins, and viral infection. ISR is the part of the innate immunity that defends against pathogen infection or environmental alteration, thereby maintaining homeostasis to avoid diseases. Here, we describe how this machinery responds to the off-target effects of ART and persistent HIV infection in both the peripheral compartments and the brain. The latter may be important for us to better understand the mechanisms of stable HIV reservoirs and HIV-associated neurocognitive disorders.