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A Compensatory Mutation Provides Resistance to Disparate HIV Fusion Inhibitor Peptides and Enhances Membrane Fusion

Wood, MP and Cole, AL and Ruchala, P and Waring, AJ and Rohan, LC and Marx, P and Tarwater, PM and Gupta, P and Cole, AM (2013) A Compensatory Mutation Provides Resistance to Disparate HIV Fusion Inhibitor Peptides and Enhances Membrane Fusion. PLoS ONE, 8 (2).

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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. © 2013 Wood et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Wood, MP
Cole, AL
Ruchala, P
Waring, AJ
Rohan, LCrohanl@pitt.eduROHANL
Marx, P
Tarwater, PM
Gupta, Ppgupta1@pitt.eduPGUPTA1
Cole, AM
Date: 5 February 2013
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 8
Number: 2
DOI or Unique Handle: 10.1371/journal.pone.0055478
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
School of Pharmacy > Pharmaceutical Sciences
Refereed: Yes
Other ID: NLM PMC3564752
PubMed Central ID: PMC3564752
PubMed ID: 23393582
Date Deposited: 14 Mar 2013 14:42
Last Modified: 23 Jun 2018 12:55
URI: http://d-scholarship.pitt.edu/id/eprint/17741

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