ADAP1 promotes latent HIV-1 reactivation by selectively tuning KRAS-ERK-AP-1 T cell signaling-transcriptional axis.
Nora-Guadalupe P RamirezJeon LeeYue ZhengLianbo LiBryce DennisDidi ChenAshwini ChallaVicente PlanellesKenneth D WestoverNeal M AltoIván D'OrsoPublished in: Nature communications (2022)
Immune stimulation fuels cell signaling-transcriptional programs inducing biological responses to eliminate virus-infected cells. Yet, retroviruses that integrate into host cell chromatin, such as HIV-1, co-opt these programs to switch between latent and reactivated states; however, the regulatory mechanisms are still unfolding. Here, we implemented a functional screen leveraging HIV-1's dependence on CD4 + T cell signaling-transcriptional programs and discovered ADAP1 is an undescribed modulator of HIV-1 proviral fate. Specifically, we report ADAP1 (ArfGAP with dual PH domain-containing protein 1), a previously thought neuronal-restricted factor, is an amplifier of select T cell signaling programs. Using complementary biochemical and cellular assays, we demonstrate ADAP1 inducibly interacts with the immune signalosome to directly stimulate KRAS GTPase activity thereby augmenting T cell signaling through targeted activation of the ERK-AP-1 axis. Single cell transcriptomics analysis revealed loss of ADAP1 function blunts gene programs upon T cell stimulation consequently dampening latent HIV-1 reactivation. Our combined experimental approach defines ADAP1 as an unexpected tuner of T cell programs facilitating HIV-1 latency escape.
Keyphrases
- antiretroviral therapy
- hiv positive
- single cell
- hiv infected
- hiv testing
- human immunodeficiency virus
- hiv aids
- hepatitis c virus
- transcription factor
- public health
- men who have sex with men
- gene expression
- high throughput
- rna seq
- signaling pathway
- cell proliferation
- south africa
- genome wide
- cell therapy
- mesenchymal stem cells
- cancer therapy
- cell death
- oxidative stress
- heat shock