Vpr.A3A chimera inhibits HIV replication.

Area of Science:

• Virology
• Molecular Biology
• Genetics

Background:

• APOBEC3 cytidine deaminases (A3F, A3G) inhibit HIV replication but are counteracted by the viral infectivity factor (Vif).
• APOBEC3A (A3A) restricts some viruses and retrotransposons but not HIV, likely due to ineffective targeting.

Purpose of the Study:

• To enhance A3A's antiviral activity against HIV and SIV by improving its cellular targeting.
• To investigate if Vif-resistant antiviral activity could be achieved through targeted delivery of A3A.

Main Methods:

• Fusion of A3A to the viral protein Vpr, which facilitates incorporation into viral cores.
• Assessing the localization of the Vpr.A3A chimera within viral particles.
• Evaluating the antiviral activity of Vpr.A3A against HIV and SIV in the presence and absence of Vif.
• Analyzing viral cDNA for G-to-A mutations to confirm DNA editing activity.

Main Results:

• The Vpr.A3A chimera, but not A3A alone, was abundantly incorporated into viral cores.
• Vpr.A3A potently restricted HIV and SIV replication, even in the presence of Vif.
• Evidence of G-to-A DNA editing in viral cDNAs confirmed the mechanism of action.
• The fusion protein did not restrict murine leukemia virus, which lacks Vpr incorporation.

Conclusions:

• Targeted delivery of A3A via Vpr fusion confers potent, Vif-resistant antiviral activity against HIV and SIV.
• This strategy utilizes DNA editing to restrict viral replication, offering a novel approach to antiviral therapy.
• Appropriate targeting is crucial for harnessing the full antiviral potential of cytidine deaminases like A3A.