HIV-1 persistence in the latently infected cell reservoir even during treatment with antiretroviral therapy (ART) eludes the HIV-1 cure. Preventing viral rebound after ART interruption is a goal of HIV-1 cure research. In Immunity, Moskovljevic et al. find that cognate antigen presentation induces HIV-1 transcription. The authors use ex vivo co-culture of autologous dendritic cells with CMV and HIV-1 Gag-reactive CD4+ T cells from 10 people on ART. By RNA sequencing, they find that exposure to cognate antigens stimulated pathways that are important for viral reactivation and were different to pathways stimulated by polyclonal stimuli. Quantification of cell-associated polyadenylated HIV-1 RNA transcripts showed an increase in HIV-1 RNA expression. To further characterize HIV-1 expression, the authors performed limiting-dilution amplification and sequencing of cell-associated HIV-1 RNA from the sorted CD154+CD69+CD4+ T cells after restimulation, in bulk and at the single HIV-1-infected cell resolution. The authors conclude that stimulation with cognate antigen or polyclonal stimuli similarly induced high RNA-producing cells, despite the low inducibility of proviruses persisting on long-term ART. The study shows that antigen recognition may affect the early viral rebound events when ART is stopped, which can inspire future studies to develop interventions to eliminate virus-producing cells.

Original reference: Immunity https://doi.org/10.1016/j.immuni.2024.11.002 (2024)