Title

RC-101, a retrocyclin-1 analogue with enhanced activity against primary HIV type 1 isolates

Authors

Authors

S. M. Owen; D. L. Rudolpil; W. Wang; A. M. Cole; A. J. Waring; R. B. Lal;R. I. Lehrer

Comments

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Abbreviated Journal Title

Aids Res. Hum. Retrovir.

Keywords

IMMUNODEFICIENCY-VIRUS TYPE-1; HERPES-SIMPLEX-VIRUS; ANTIMICROBIAL; PEPTIDES; ALPHA-DEFENSINS; BETA-DEFENSINS; THETA-DEFENSINS; HUMAN; ALPHA-DEFENSIN-1; MESSENGER-RNA; HOST-DEFENSE; SUBTYPE-C; Immunology; Infectious Diseases; Virology

Abstract

Rhesus macaques express three theta-defensins (RTDs 1-3), cyclic octadecapeptides with antiviral and lectin-like properties. Corresponding theta-defensin genes exist and are expressed in humans, but a signal sequence mutation prevents the formation of mature theta-defensin peptides. Retrocyclin-1 is a theta-defensin peptide whose precursor is encoded by human theta-defensin pseudogenes. It can protect human peripheral blood lymphocytes from infection by R5 and X4 strains of HIV-1, and provides a molecular template for designing novel antiviral agents. In this study, we used JC53-BL reporter cells to assess the activity of retrocyclin-1 (RC-100) and several analogues against primary HIV-1 isolates, including R5 and R5X4 strains of subtypes A-D, CRF-01_AE, and recombinants. Each analogue differed from retrocyclin-1 by a single amino, acid substitution: Gly --> Tyr in RC-106, RC-115, and RC-116, and Arg --> Lys in RC-101. Although the modification in RC-101 was chemically conservative, this peptide was significantly more potent than retrocyclin-1 across the panel of primary isolates. We performed surface plasmon resonance binding studies, using recombinant gp120 and CD4 produced in insect cells. Although RC-100 and RC-101 bound gp120 LAV/IIIB with a K-d of 30-35 nM, they bound gp120 from CRF-01_AE strains (CM 235 and 93TH975.15) with K-d values of 200-750 nM. Overall, our findings suggest that clade-related differences in gp120 glycosylation impact the ability of retrocyclin-1 to bind this viral glycoprotein, and modulate the peptides' ability to prevent HIV-1 infection. The performance of RC-101 suggests that additional "engineering" could further enhance the antiviral properties of theta-defensins.

Journal Title

Aids Research and Human Retroviruses

Volume

20

Issue/Number

11

Publication Date

1-1-2004

Document Type

Article

Language

English

First Page

1157

Last Page

1165

WOS Identifier

WOS:000225576400003

ISSN

0889-2229

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