Inhibition of ATM-directed antiviral responses by HIV-1 Vif.
Hoi Tong WongAdeline M LuperchioSean RileyDaniel J SalamangoPublished in: PLoS pathogens (2023)
Emerging evidence indicates that HIV-1 hijacks host DNA damage repair (DDR) pathways to facilitate multiple facets of virus replication. Canonically, HIV-1 engages proviral DDR responses through the accessory protein Vpr, which induces constitutive activation of DDR kinases ATM and ATR. However, in response to prolonged DDR signaling, ATM directly induces pro-inflammatory NF-κB signaling and activates multiple members of the TRIM family of antiviral restriction factors, several of which have been previously implicated in antagonizing retroviral and lentiviral replication. Here, we demonstrate that the HIV-1 accessory protein Vif blocks ATM-directed DNA repair processes, activation of NF-κB signaling responses, and TRIM protein phosphorylation. Vif function in ATM antagonism occurs in clinical isolates and in common HIV-1 Group M subtypes/clades circulating globally. Pharmacologic and functional studies combine to suggest that Vif blocks Vpr-directed activation of ATM but not ATR, signifying that HIV-1 utilizes discrete strategies to fine-tune DDR responses that promote virus replication while simultaneously inhibiting immune activation.
Keyphrases
- dna damage
- dna repair
- antiretroviral therapy
- hiv positive
- hiv infected
- hiv testing
- dna damage response
- human immunodeficiency virus
- hepatitis c virus
- hiv aids
- men who have sex with men
- oxidative stress
- signaling pathway
- south africa
- protein protein
- cell proliferation
- amino acid
- inflammatory response
- gene therapy
- case control