title: A compensatory mutation provides resistance to disparate HIV fusion inhibitor peptides and enhances membrane fusion.
abstract: Fusion inhibitors are a class of antiretroviral drugs used to prevent entry of HIV into host cells. Many of the fusion inhibitors being developed, including the drug enfuvirtide, are peptides designed to competitively inhibit the viral fusion protein gp41. With the emergence of drug resistance, there is an increased need for effective and unique alternatives within this class of antivirals. One such alternative is a class of cyclic, cationic, antimicrobial peptides known as θ-defensins, which are produced by many non-human primates and exhibit broad-spectrum antiviral and antibacterial activity. Currently, the θ-defensin analog RC-101 is being developed as a microbicide due to its specific antiviral activity, lack of toxicity to cells and tissues, and safety in animals. Understanding potential RC-101 resistance, and how resistance to other fusion inhibitors affects RC-101 susceptibility, is critical for future development. In previous studies, we identified a mutant, R5-tropic virus that had evolved partial resistance to RC-101 during in vitro selection. Here, we report that a secondary mutation in gp41 was found to restore replicative fitness, membrane fusion, and the rate of viral entry, which were compromised by an initial mutation providing partial RC-101 resistance. Interestingly, we show that RC-101 is effective against two enfuvirtide-resistant mutants, demonstrating the clinical importance of RC-101 as a unique fusion inhibitor. These findings both expand our understanding of HIV drug-resistance to diverse peptide fusion inhibitors and emphasize the significance of compensatory gp41 mutations.
authors: Department of Molecular Biology and Microbiology, Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, Florida, United States of America.
authors: Matthew P
authors: MP
authors: Wood
authors: Amy L
authors: AL
authors: Cole
authors: Piotr
authors: P
authors: Ruchala
authors: Alan J
authors: AJ
authors: Waring
authors: Lisa C
authors: LC
authors: Rohan
authors: Preston
authors: P
authors: Marx
authors: Patrick M
authors: PM
authors: Tarwater
authors: Phalguni
authors: P
authors: Gupta
authors: Alexander M
authors: AM
authors: Cole
mesh_terms: D002460:Cell Line; D024882:Drug Resistance, Viral / Q000235:genetics; D015700:HIV Envelope Protein gp41 / Q000235:genetics*; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D006801:Humans; D008561:Membrane Fusion / Q000187:drug effects*; D009154:Mutation; D010455:Peptides / Q000494:pharmacology
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010455:Peptides; C450143:RC 101
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