HIV-1 adapts to a retrocyclin with cationic amino acid substitutions that reduce fusion efficiency of grp41

    Authors

    A. L. Cole; O. O. Yang; A. D. Warren; A. J. Waring; R. I. Lehrer;A. M. Cole

    Comments

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    Abbreviated Journal Title

    J. Immunol.

    Keywords

    IMMUNODEFICIENCY-VIRUS TYPE-1; THETA-DEFENSINS; ALPHA-DEFENSINS; ANTIMICROBIAL PEPTIDES; SMALL-MOLECULE; RESISTANCE; INHIBITOR; CELLS; ENTRY; TYPHIMURIUM; Immunology

    Abstract

    Retrocyclin (RC)-101 is a cationic theta-defensin that inhibits HIV-1 entry. Passaging HIV-1(BAL) under selective pressure by this cyclic minidefensin resulted in only a 5- to 10-fold decrease in viral susceptibility to RC-101. Emergent viral isolates had three amino acid substitutions in their envelope glycoprotein. One was in a CD4-binding region of gp120, and the others were in the heptad repeat (HR) domains of gp41 (HR1 and HR2). Each mutation replaced an electroneutral or electronegative residue with one that was positively charged. These mutations were evaluated either alone or in combination in a single-round viral entry assay. Although the mutation in gp120 did not affect viral entry, the mutation in HR1 of gp41 conferred relative resistance to RC-101. Interestingly, the envelope with the HR2 mutation was less efficient and became codependent on the presence of RC-101 for entry. The adaptive response of HIV-1 to this cationic host defense peptide resembles the responses of bacteria that modulate their surface or membrane charge to evade analogous host defense peptides. These findings also suggest that interactions between theta-defensins and gp41 may contribute to the ability of these cyclic minidefensins to prevent HIV-1 entry into target cells.

    Journal Title

    Journal of Immunology

    Volume

    176

    Issue/Number

    11

    Publication Date

    1-1-2006

    Document Type

    Article

    Language

    English

    First Page

    6900

    Last Page

    6905

    WOS Identifier

    WOS:000237754200057

    ISSN

    0022-1767

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