Poly (ADP-ribose) polymerase-1 regulates HIV-1 replication in human CD4+ T cells

Area of Science:

• Virology
• Cellular Biology
• Immunology

Background:

• Cellular processes can counteract viral replication, offering targets for infection control.
• The role of poly (ADP-ribose) polymerase-1 (PARP-1) in HIV-1 infection is controversial, with prior studies limited by pseudotyped viruses.
• Understanding host-pathogen interactions is crucial for developing antiviral strategies.

Purpose of the Study:

• To investigate the effect of PARP-1 deficiency or inhibition on HIV-1 replication in human CD4+ T cells.
• To elucidate the mechanism by which PARP-1 influences HIV-1 infectivity and viral production.
• To determine the specific domains and activities of PARP-1 involved in regulating HIV-1.

Main Methods:

• Utilized PARP-1 knockout SUP-T1 cells and PARP-1 inhibitors targeting DNA-binding and catalytic activities.
• Performed mutagenesis analysis to assess the role of PARP-1 domains in anti-HIV-1 activity.
• Assessed HIV-1 replication, infectivity, and virion-associated Env levels in producer cells and purified virions.
• Investigated the role of viral Env in PARP-1's effect on infectivity using Env-deleted viruses.

Main Results:

• PARP-1 knockout and DNA-binding inhibition enhanced HIV-1 replication and infectivity.
• Inhibitors targeting PARP-1 catalytic activity did not affect viral replication.
• Mutagenesis confirmed the DNA-binding domain, not poly-ADP-ribosylation activity, is crucial for PARP-1's anti-HIV-1 function.
• PARP-1 acts during the production phase, increasing the infectivity of newly produced HIV-1.
• PARP-1 deficiency led to increased virion-associated Env, dependent on viral Env, but did not alter Env expression in producer cells.

Conclusions:

• PARP-1 antagonism enhances HIV-1 infectivity, primarily by increasing virion-associated Env.
• The DNA-binding activity of PARP-1, not its catalytic activity, is essential for its anti-HIV-1 role.
• PARP-1 is identified as a host factor regulating HIV-1 infectivity, with implications for understanding viral transmission and vaccine development.