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Journal of Virology, June 2002, p. 6277-6292, Vol. 76, No. 12
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.12.6277-6292.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Increased CCR5 Affinity and Reduced CCR5/CD4 Dependence of a Neurovirulent Primary Human Immunodeficiency Virus Type 1 Isolate

Paul R. Gorry,1,2,{dagger} Joann Taylor,3 Geoffrey H. Holm,1,2 Andrew Mehle,1,2 Tom Morgan,4 Mark Cayabyab,1,2 Michael Farzan,1,2 Hui Wang,1 Jeanne E. Bell,5 Kevin Kunstman,3 John P. Moore,4 Steven M. Wolinsky,3 and Dana Gabuzda1,6*

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute,1 Departments of Pathology,2 Neurology, Harvard Medical School, Boston, Massachusetts,6 Department of Medicine, Northwestern University Medical School, Chicago, Illinois,3 Weill Medical College of Cornell University, New York, New York,4 Department of Pathology, University of Edinburgh, United Kingdom5

Received 13 December 2001/ Accepted 15 March 2002

Most human immunodeficiency virus type 1 (HIV-1) viruses in the brain use CCR5 as the principal coreceptor for entry into a cell. However, additional phenotypic characteristics are necessary for HIV-1 neurotropism. Furthermore, neurotropic strains are not necessarily neurovirulent. To better understand the determinants of HIV-1 neurovirulence, we isolated viruses from brain tissue samples from three AIDS patients with dementia and HIV-1 encephalitis and analyzed their ability to induce syncytia in monocyte-derived macrophages (MDM) and neuronal apoptosis in primary brain cultures. Two R5X4 viruses (MACS1-br and MACS1-spln) were highly fusogenic in MDM and induced neuronal apoptosis. The R5 viruses UK1-br and MACS2-br are both neurotropic. However, only UK1-br induced high levels of fusion in MDM and neuronal apoptosis. Full-length Env clones from UK1-br required lower CCR5 and CD4 levels than Env clones from MACS2-br to function efficiently in cell-to-cell fusion and single-round infection assays. UK1-br Envs also had a greater affinity for CCR5 than MACS2-br Envs in binding assays. Relatively high levels of UK1-br and MACS2-br Envs bound to CCR5 in the absence of soluble CD4. However, these Envs could not mediate CD4-independent infection, and MACS2-br Envs were unable to mediate fusion or infection in cells expressing low levels of CD4. The UK1-br virus was more resistant than MACS2-br to inhibition by the CCR5-targeted inhibitors TAK-779 and Sch-C. UK1-br was more sensitive than MACS2-br to neutralization by monoclonal antibodies (2F5 and immunoglobulin G1b12 [IgG1b12]) and CD4-IgG2. These results predict the presence of HIV-1 variants with increased CCR5 affinity and reduced dependence on CCR5 and CD4 in the brains of some AIDS patients with central nervous system disease and suggest that R5 variants with increased CCR5 affinity may represent a pathogenic viral phenotype contributing to the neurodegenerative manifestations of AIDS.

* Corresponding author. Mailing address: Dana-Farber Cancer Institute, 44 Binney St., JF816, Boston, MA 02115. Phone: (617) 632-2154. Fax: (617) 632-3113. E-mail: dana_gabuzda{at}dfci.harvard.edu.

{dagger} Present address: Department of Microbiology and Immunology, University of Melbourne, Victoria, Australia.

Journal of Virology, June 2002, p. 6277-6292, Vol. 76, No. 12
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.12.6277-6292.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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