Mechanisms of CCR5 Agonist/Antagonist Inhibition of HIV-1 Entry and In Vitro Selection of Virus Resistant to Maraviroc

Entry inhibitors represent a new class of antiretrovirals for the treatment of HIV-1 infection. These inhibitors target interactions of the viral envelope glycoprotein with host cell receptors as well as fusion of the viral and host cell membranes. Extensive development of inhibitors that target CCR5, a cellular coreceptor required for viral entry, has resulted in molecules with potent antiviral activity. However, diverse HIV-1 isolates exhibit a wide variation in intrinsic sensitivity to these inhibitors due to factors including the heterogeneity of the envelope glycoprotein, affinity of the envelope for cellular receptors, and rate of entry. The studies presented here demonstrate competitive binding between the envelope glycoprotein and inhibitor for CCR5 is a major mechanism involved in sensitivity to PSC-RANTES. Although downregulation of coreceptor expression from the cell surface was instigated by PSC-RANTES binding, this effect was of short duration and competitive binding modulated viral sensitivity and resistance over time. In addition, in vitro selection of viruses resistant to the CCR5 antagonist maraviroc highlighted a novel mechanism of HIV-1 resistance to this type of inhibitor. Unlike previous studies, resistance was unrelated to changes in the V3 region of the glycoprotein. Rather, resistant virus harbored mutations in the CD4 binding site of the envelope glycoprotein, demonstrated enhanced affinity for binding to CD4, increased replicative fitness capacity, and increased rates of viral entry. These findings contribute to the broader knowledge of inhibition of HIV-1 entry, receptor affinity relationships, and adaptive mechanisms of HIV-1 virus in response to treatment with CCR5 entry inhibitors.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Molecular Biology and Microbiology

Grantor dc:publisher

Case Western Reserve University School of Graduate Studies

Year dc:date

2013

Author dc:creator

• Ratcliff, Annette N.

Contributors dc:contributor

• Karn, Jonathan
• Arts, Eric

• Molecular Biology
• Virology
• HIV-1
• envelope
• maraviroc
• resistance
• entry

Statement dc:rights

• unrestricted
• This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

Language dc:language

English

Repository record dc:identifier

http://rave.ohiolink.edu/etdc/view?acc_num=case1354647096

OAI identifier oai:identifier

oai:etd.ohiolink.edu:case1354647096