Elucidating Novel Mechanism of HIV-1 Evading APOBEC3G Antiviral Function Through Selective Viral RNA Packaging

HIV-1/AIDS can be managed with antiretroviral drugs, but treatment is lifelong, and interruption leads to viral rebound. Side effects, patient compliance, and viral resistance limit current therapy's effectiveness. To combat the rise of multidrug-resistant HIV-1, developing drugs targeting novel viral mechanisms is crucial. APOBEC3G (A3G) restricts HIV-1 replication by inhibiting viral cDNA production and inducing G-to-A hypermutations in the viral genome. While HIV-1 uses Vif to counteract A3G, evidence shows that A3G activity remains detectable in wild-type viruses. Our recent publication revealed that HIV-1 selectively packages viral genomic RNA with a lower A3G-related G to A mutation rate, suggesting a novel mechanism of HIV evades A3G antiviral function. In this application, we propose to tackle the novel mechanism of how HIV evades A3G antiviral function by preferential packaging unmutated or less-mutated genomes to its particles. We hypothesize that HIV selectively packages viral RNA with lower A3G-related G-to-A mutation rates by avoiding packaging viral RNA with mutations in crucial packaging elements like the [UUUU]:[GGAG] helical element and GGG tract. The study aims to: 1) Compare A3G-related G-to-A mutation profiles in infected cells and released virions, focusing on key packaging elements, and 2) Investigate the impact of G-to-A mutations in these regions on viral RNA packaging efficiency using mutagenesis methods. The novelty of this research lies in exploring an unexplored RNA-level mechanism of HIV evasion. Understanding this mechanism could significantly advance our knowledge of HIV pathogenesis, potentially leading to new antiretroviral therapies targeting the viral RNA packaging process and improving gene delivery vector development. Project Number: 1R21AI191964-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Bindong Liu | Institution: MEHARRY MEDICAL COLLEGE, NASHVILLE, TN | Award Amount: $400,125 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 IIDA-U (02)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21AI19196401