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…

Federal Grant Award Summary

Meharry Medical College received a $400,125 Project Grant award from the National Institute of Allergy and Infectious Diseases (NIAID) under the Allergy and Infectious Diseases Research program (CFDA 93.855), effective June 17, 2025, through May 31, 2027. The award funds research investigating a novel mechanism by which HIV-1 (Human Immunodeficiency Virus-1) evades the antiviral function of APOBEC3G (A3G), a cellular restriction factor that normally inhibits viral replication and induces mutations in the viral genome. The research aims to elucidate how HIV-1 selectively packages viral RNA with lower mutation rates by avoiding genomic regions containing critical packaging elements, thereby circumventing A3G-mediated antiviral activity.

The research deliverables include comparative analyses of A3G-related G-to-A mutation profiles in infected cells versus released virions, with particular focus on key packaging elements such as the [UUUU]:[GGAG] helical element and GGG tract, as well as mutagenesis studies to assess the impact of G-to-A mutations on viral RNA packaging efficiency. The findings are expected to advance understanding of HIV pathogenesis and potentially inform development of novel antiretroviral therapies targeting the viral RNA packaging process, with secondary applications to gene delivery vector development.

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.