Written by Leanna Bai ‘25
Edited by Josephine Chen ‘24
Throughout evolutionary history, HIV has been evolving in tandem with the human population. Moving from chimpanzees to humans in the 1800s, this virus is involved in the extermination of the body’s CD4 immune cells, resulting in a progressive weakening of the body’s defenses (1). With recent developments in antiretroviral therapies, many people diagnosed with HIV are able to live long, mostly healthy lives; however, nearly a million people every year continue to die worldwide from lack of treatment or delayed detection/medication (2). As a result, understanding the interaction between the virus and the human body is still extremely necessary, particularly on a molecular level, for developing novel drug treatments.
Recently, Li et al. from the University of California, San Francisco have uncovered the structural basis for the interaction of two fascinating HIV-implicated proteins: the human protein A3G and the viral Vif (3). This discovery is particularly interesting due to the “molecular arms race” that occurs between these two proteins, which have been evolving in opposition to each other, one mutating to overcome the other (3). HIV and other RNA viruses operate by hijacking CD4 cell machinery to replicate their viral genome; to stop the production of more viruses, the protein A3G mutates the viral genetic material. Additionally, it inhibits reverse transcription, a process integral to the replication of RNA viruses. As a result, HIV is unable to produce more of itself. However, the viral protein Vif responds by tagging A3G with ubiquitin, a signaling molecule that causes the host cell to activate its own defense mechanism and degrade A3G.
A3G and Vif, therefore, appear to exhibit a unique “cat-and-mouse” relationship, but scientists had yet to understand the structural basis for their interactions until Li et al. uncovered the crystal structure of A3G and Vif bound together. Using cryo-EM, a technique that uncovers the three-dimensional structures of molecules, the researchers determined that a small strand of RNA mediates the interaction between these two proteins, bridging A3G and Vif (3). In vivo, this strand of RNA would likely come from the HIV virus. Both Vif and A3G recognize the RNA molecule through unique binding sites, and the virus uses this interaction to degrade A3G. Thus, the human cell’s defense mechanism is defeated in this scenario.
Interestingly, the researchers also highlight a specific RNA-binding region of A3G that has been conserved, meaning that the amino acids in that location have not mutated over evolutionary history (3). Perhaps, according to scientists, this region is critical in A3G’s ability to “escape” Vif binding and subsequent ubiquitin tagging and could be exploited pharmaceutically (4).
Overall, the elucidation of the molecular mechanisms of the A3G-Vif interaction is clinically significant — as of now, there are no HIV therapeutics that inhibit Vif, but designing a drug that blocks its binding to A3G could serve as an avenue for limiting HIV replication in the body. Furthermore, the viral load of HIV patients could significantly decrease, increasing patient survival rate and improving their quality of life.
References
About HIV. Centers for Disease Control and Prevention [Internet]. 2022 June 30 [cited 2023 Apr 10]. Available from: https://www.cdc.gov/hiv/basics/whatishiv.html#:~:text=Studies%20show%20that%20HIV%20may,contact%20with%20their%20infected%20blood
HIV Treatment: The Basics. HIVinfo.NIH.gov [Internet]. 2021 Aug 16 [cited 2023 Apr 10]. Available from: https://hivinfo.nih.gov/understanding-hiv/fact-sheets/hiv-treatment-basics#:~:text=treatment%20for%20HIV%3F-,The%20treatment%20for%20HIV%20is%20called%20antiretroviral%20therapy%20(ART)
Li, YL, Langley, CA, Azumaya, CM et al. The structural basis for HIV-1 Vif antagonism of human APOBEC3G. Nature. 2023, February, 8;615:728–733.
Beans, C. Structure of dueling proteins points to HIV origins, treatment avenues. PNAS Journal Club [Internet]. 2023 Feb 18 [cited 2023 Apr 10]. Available from: https://www.pnas.org/post/journal-club/structure-dueling-proteins-points-hiv-origins-treatment-avenues
[Image] HIV-budding-Color.jpeg [Internet] [cited 2023 Apr 10] Available from: https://commons.wikimedia.org/wiki/File:HIV-budding-Color.jpg