ADAP1 promotes latent HIV-1 reactivation by selectively tuning KRAS–ERK–AP-1 T cell signaling-transcriptional axis

Nora-Guadalupe P. Ramirez, Jeon Lee, Yue Zheng, Lianbo Li, Bryce Dennis, Didi Chen, Ashwini Challa, Vicente Planelles, Kenneth D. Westover, Neal M. Alto and Iván D’Orso ()
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Nora-Guadalupe P. Ramirez: The University of Texas Southwestern Medical Center
Jeon Lee: The University of Texas Southwestern Medical Center
Yue Zheng: University of Utah School of Medicine
Lianbo Li: The University of Texas Southwestern Medical Center
Bryce Dennis: The University of Texas Southwestern Medical Center
Didi Chen: The University of Texas Southwestern Medical Center
Ashwini Challa: The University of Texas Southwestern Medical Center
Vicente Planelles: University of Utah School of Medicine
Kenneth D. Westover: The University of Texas Southwestern Medical Center
Neal M. Alto: The University of Texas Southwestern Medical Center
Iván D’Orso: The University of Texas Southwestern Medical Center

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-28772-0

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