Journal article

The magnitude of HIV-1 resistance to the CCR5 antagonist maraviroc may impart a differential alteration in HIV-1 tropism for macrophages and T-cell subsets

Jacqueline K Flynn, Geza Paukovics, Miranda S Moore, Anne Ellett, Lachlan R Gray, Renee Duncan, Hamid Salimi, Becky Jubb, Mike Westby, Damian FJ Purcell, Sharon R Lewin, Benhur Lee, Melissa J Churchill, Paul R Gorry, Michael Roche



Human immunodeficiency virus type 1 (HIV-1) resistance to CCR5 antagonists, including maraviroc (MVC), results from alterations in the HIV-1 envelope glycoproteins (Env) enabling recognition of antagonist-bound CCR5. Here, we characterized tropism alterations for CD4+ T-cell subsets and macrophages by Envs from two subjects who developed MVC resistance in vivo, which displayed either relatively efficient or inefficient recognition of MVC-bound CCR5. We show that MVC-resistant Env with efficient recognition of drug-bound CCR5 displays a tropism shift for CD4+ T-cell subsets associated with increased infection of central memory T-cells and reduced infection of effector memory and transitional ..

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Awarded by Australian National Health and Medical Research Council

Funding Acknowledgements

We thank J. Sodroski for providing pSVIII-YU-2 Env plasmid and for providing pCMV Delta P1 Delta envpA and pHIV-1Luc plasmids. We also thank D. Kabat for providing JC53 cells, 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 are also grateful to J. Mori and M. Lewis for their past contributions to this work, J. Demarest for helpful comments, and T. Spellman for advice with statistical analysis. Maraviroc was provided by Pfizer. This study was supported by a grant from the Australian National Health and Medical Research Council to PRG, MJC and SRL (1006534). PRG was the recipient of an Australian National Health and Medical Research Council (NHMRC) Level 2 Biomedical Career Development Award, and is now supported by an Australian Research Council (ARC) Future Fellowship (FT2). LRG is the recipient of an Australian NHMRC Postdoctoral Training Fellowship. HS is supported by a Postgraduate Research Scholarship from the Iranian Ministry of Health and Medical Education. SRL is the recipient of a NHMRC Practitioner Fellowship. The authors gratefully acknowledge the contribution to this work of the Victorian Operational Infrastructure Support Program received by the Burnet Institute. Pfizer assumes no responsibility for the validation and storage of the data shown in Figs. 1-4 and Table 2.