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A compensatory mutation provides resistance to disparate HIV fusion inhibitor peptides and enhances membrane fusion
- Source :
- PLoS ONE, Vol 8, Iss 2, p e55478 (2013), PLoS ONE
- Publication Year :
- 2013
- Publisher :
- Public Library of Science (PLoS), 2013.
-
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.
- Subjects :
- Viral Diseases
Enfuvirtide
Viral Entry
Urology
Antimicrobial peptides
lcsh:Medicine
Drug resistance
Biology
Gp41
Microbiology
Membrane Fusion
Cell Line
03 medical and health sciences
Viral entry
HIV Fusion Inhibitors
Virology
Drug Resistance, Viral
medicine
Humans
lcsh:Science
030304 developmental biology
0303 health sciences
Multidisciplinary
Cell fusion
030306 microbiology
Genitourinary Infections
lcsh:R
Immunity
Lipid bilayer fusion
HIV
Obstetrics and Gynecology
Fusion protein
Innate Immunity
HIV Envelope Protein gp41
3. Good health
Infectious Diseases
Mutation
Medicine
Clinical Immunology
lcsh:Q
Peptides
Viral Transmission and Infection
medicine.drug
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 8
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....c760885c445e3ffdf2558380aa97470a