TDP-43 Controls HIV-1 Viral Production and Virus Infectiveness.

Area of Science:

• Virology
• Molecular Biology
• Cell Biology

Background:

• The transactive response DNA-binding protein (TDP-43) stabilizes histone deacetylase 6 (HDAC6), an anti-HIV-1 factor.
• TDP-43 influences cell permissivity to HIV-1 by interacting with HDAC6 and affecting tubulin acetylation.

Purpose of the Study:

• To investigate the role of TDP-43 in the late stages of the HIV-1 viral cycle.
• To elucidate the functional relationship between TDP-43, HDAC6, and HIV-1 production and infectivity.

Main Methods:

• Overexpression of TDP-43 in virus-producing cells.
• TDP-43 knockdown experiments.
• Analysis of HDAC6, HIV-1 Pr55Gag, Vif protein levels, and α-tubulin acetylation.
• Assessment of viral particle production and infectivity.
• Use of a nuclear localization signal (NLS)-TDP-43 mutant.

Main Results:

• TDP-43 overexpression stabilized HDAC6, promoted autophagic clearance of HIV-1 Pr55Gag and Vif, inhibited viral production, and reduced virion infectivity.
• A TDP-43 NLS mutant failed to control HIV-1 production and infection.
• TDP-43 knockdown decreased HDAC6 expression, increased HIV-1 Vif and Pr55Gag levels, enhanced virion production, and boosted virus infectious capacity.
• A direct correlation was observed between Vif and Pr55Gag content in virions and their infectivity.

Conclusions:

• The TDP-43/HDAC6 axis is crucial for controlling HIV-1 viral production and infectivity.
• TDP-43 plays a significant role in regulating the late stages of the HIV-1 lifecycle.
• Modulating the TDP-43/HDAC6 pathway offers a potential strategy for controlling HIV-1 infection.