JVI Accepts, published online ahead of print on 24 June 2009

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J. Virol. doi:10.1128/JVI.00780-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Virus Entry via the Alternative Coreceptors CCR3 and FPRL1 Differs by Human Immunodeficiency Virus Type 1 Subtype

R. Nedellec, M. Coetzer, N. Shimizu, H. Hoshino, V. R. Polonis, L. Morris, U. E. A. Martensson, J. Binley, J. Overbaugh, and D. E. Mosier^*

Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037; Department of Virology and Preventive Medicine, Gunma University Graduate School of Medicine, Showa-machi, Maebashi, Gunma 371-8511, Japan; Division of Retrovirology, Walter Reed Army Institute of Research, Washington, DC 20307; National Institute for Communicable Diseases, Johannesburg, Private Bag X4, Sandringham 2131, Johannesburg, South Africa; Division of Molecular Neurobiology, Wallenberg Neuroscience Center, Lund University, SE-223 62, Sweden; Torrey Pines Institute for Molecular Studies, San Diego, CA 92121; Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109

^* To whom correspondence should be addressed. Email: dmosier{at}scripps.edu.

HIV-1 infects target cells by binding to CD4 and a chemokine receptor, most commonly CCR5. CXCR4 is a frequent alternative coreceptor (CoR) in subtype B and D HIV-1 infection, but the importance of many other alternative CoR remains elusive. We have analyzed HIV-1 envelope proteins (Env) from 66 individuals infected with the major subtypes of HIV-1 to determine if virus entry into highly permissive NP-2 cell lines expressing most known alternative CoR differed by HIV-1 subtype. We also performed linear regression analysis to determine if virus entry via the major CoR CCR5 correlated with use of any alternative CoR, and if this correlation differed by subtype. Virus pseudotyped with subtype B Env showed robust entry via CCR3 that was highly correlated with CCR5 entry efficiency. By contrast, viruses pseudotyped with subtype A and C Env were able to use the recently described alternative CoR FPRL1 more efficiently than CCR3, and use of FPRL1 was correlated with CCR5 entry. Subtype D Env was unable to use either CCR3 or FPRL1 efficiently, a unique pattern of alternative CoR use. These results suggest that each subtype of circulating HIV-1 may be subject to somewhat different selective pressures for Env-mediated entry into target cells, and suggest that CCR3 may be used as a surrogate CoR by subtype B while FPRL1 may be used as a surrogate CoR by subtype A and C. These data may provide insight into development of resistance to CCR5-targeted entry inhibitors and alternative entry pathways for each HIV-1 subtype.