Title

Retrocyclin RC-101 overcomes cationic mutations on the heptad repeat 2 region of HIV-1 gp41

Authors

Authors

C. A. Fuhrman; A. D. Warren; A. J. Waring; S. M. Dutz; S. Sharma; R. I. Lehrer; A. L. Cole;A. M. Cole

Comments

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Abbreviated Journal Title

Febs J.

Keywords

AUTODOCK; defensin; HIV-1; innate immunity; retrocyclin; IMMUNODEFICIENCY-VIRUS TYPE-1; 6-HELIX BUNDLE FORMATION; ENV-MEDIATED; FUSION; ENVELOPE GLYCOPROTEIN; ALPHA-DEFENSINS; THETA-DEFENSINS; AUTOMATED DOCKING; CORE STRUCTURE; SWISS-MODEL; PEPTIDE; Biochemistry & Molecular Biology

Abstract

Retrocyclin RC-101, a theta-defensin with lectin-like properties, potently inhibits infection by many HIV-1 subtypes by binding to the heptad repeat 2 (HR2) region of glycoprotein 41 (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 Los Alamos National Laboratory (New Mexico, USA) for residue variations in the heptad repeat 1 (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 1.25-10 mu g.mL(-1) RC-101. Apart from 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.

Journal Title

Febs Journal

Volume

274

Issue/Number

24

Publication Date

1-1-2007

Document Type

Article

Language

English

First Page

6477

Last Page

6487

WOS Identifier

WOS:000251385800022

ISSN

1742-464X

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