Journal article

Analysis of Clinical HIV-1 Strains with Resistance to Maraviroc Reveals Strain-Specific Resistance Mutations, Variable Degrees of Resistance, and Minimal Cross-Resistance to Other CCR5 Antagonists

Jacqueline K Flynn, Paula Ellenberg, Renee Duncan, Anne Ellett, Jingling Zhou, Jasminka Sterjovski, Kieran Cashin, Katharina Borm, Lachlan R Gray, Marilyn Lewis, Becky Jubb, Mike Westby, Benhur Lee, Sharon R Lewin, Melissa Churchill, Michael Roche, Paul R Gorry

AIDS RESEARCH AND HUMAN RETROVIRUSES | MARY ANN LIEBERT, INC | Published : 2017

Abstract

Maraviroc (MVC) is an allosteric inhibitor of human immunodeficiency virus type 1 (HIV-1) entry, and is the only CCR5 antagonist licensed for use as an anti-HIV-1 therapeutic. It acts by altering the conformation of the CCR5 extracellular loops, rendering CCR5 unrecognizable by the HIV-1 envelope (Env) glycoproteins. This study aimed to understand the mechanisms underlying the development of MVC resistance in HIV-1-infected patients. To do this, we obtained longitudinal plasma samples from eight subjects who experienced treatment failure with phenotypically verified, CCR5-tropic MVC resistance. We then cloned and characterized HIV-1 Envs (n = 77) from plasma of pretreatment (n = 36) and trea..

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Grants

Awarded by Australian National Health and Medical Research Council (NHMRC)


Funding Acknowledgements

This study was supported by a grant from the Australian National Health and Medical Research Council (NHMRC) to PRG (1059394). We thank J. Sodroski for providing the pSVIII-Env plasmid, pCMV Delta P1 Delta envpA and pHIV-1Luc plasmids, N. Shimizu and H. Hoshino for permission to use NP2-CD4/CCR5 cells, and D. Mosier and R. Nedellec for supplying the NP2-CD4/CCR5 cells. We also thank J. Demarest and F. Drummond from ViiV Healthcare for providing MVC, for permission to use MOTIVATE trial clinical data and Env amplicons derived from clinical samples, and for helpful comments on the article. TAK-779 was obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH.