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RETROCYCLIN RC-101 OVERCOMES CATIONIC MUTATIONS ON THE HEPTAD REPEAT 2 OF HIV-1 GP41

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Date Issued:
2007
Abstract/Description:
Retrocyclin RC-101, a θ-defensin with lectin-like properties, potently inhibits infection by many HIV-1 subtypes by binding to the heptad repeat (HR)-2 region of gp41 and preventing six-helix bundle formation. In the present study, we used in silico computational exploration to identify residues of HR2 that interacted with RC-101 and then analyzed the HIV-1 Sequence Database at LANL for residue variations in the HR1 and HR2 segments that could plausibly impart in vivo resistance. Docking RC-101 to gp41 peptides in silico confirmed its strong preference for HR2 over HR1, and implicated residues crucial for its ability to bind HR2. We mutagenized these residues in pseudotyped HIV-1 JR.FL reporter viruses, and subjected them to single round replication assays in the presence of 1.25-10ug/ml RC-101. Except for one mutant that was partially resistant to RC-101, the other pseudotyped viruses with single-site cationic mutations in HR2 manifested absent or impaired infectivity or retained wild-type susceptibility to RC-101. Overall, these data suggest that most mutations capable of rendering HIV-1 resistant to RC-101 will also exert deleterious effects on the ability of HIV-1 to initiate infections - an interesting and novel property for a potential topical microbicide.
Title: RETROCYCLIN RC-101 OVERCOMES CATIONIC MUTATIONS ON THE HEPTAD REPEAT 2 OF HIV-1 GP41.
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Name(s): Fuhrman, Christopher, Author
Cole, Alexander, Committee Chair
University of Central Florida, Degree Grantor
Type of Resource: text
Date Issued: 2007
Publisher: University of Central Florida
Language(s): English
Abstract/Description: Retrocyclin RC-101, a θ-defensin with lectin-like properties, potently inhibits infection by many HIV-1 subtypes by binding to the heptad repeat (HR)-2 region of gp41 and preventing six-helix bundle formation. In the present study, we used in silico computational exploration to identify residues of HR2 that interacted with RC-101 and then analyzed the HIV-1 Sequence Database at LANL for residue variations in the HR1 and HR2 segments that could plausibly impart in vivo resistance. Docking RC-101 to gp41 peptides in silico confirmed its strong preference for HR2 over HR1, and implicated residues crucial for its ability to bind HR2. We mutagenized these residues in pseudotyped HIV-1 JR.FL reporter viruses, and subjected them to single round replication assays in the presence of 1.25-10ug/ml RC-101. Except for one mutant that was partially resistant to RC-101, the other pseudotyped viruses with single-site cationic mutations in HR2 manifested absent or impaired infectivity or retained wild-type susceptibility to RC-101. Overall, these data suggest that most mutations capable of rendering HIV-1 resistant to RC-101 will also exert deleterious effects on the ability of HIV-1 to initiate infections - an interesting and novel property for a potential topical microbicide.
Identifier: CFE0001707 (IID), ucf:47333 (fedora)
Note(s): 2007-08-01
M.S.
Burnett College of Biomedical Sciences, Department of Molecular Biology and Microbiology
Masters
This record was generated from author submitted information.
Subject(s): HIV
retrocyclin
defensin
innate immunity
docking
Persistent Link to This Record: http://purl.flvc.org/ucf/fd/CFE0001707
Restrictions on Access: private 2007-06-01
Host Institution: UCF

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