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J Virol, July 1998, p. 6040-6047, Vol. 72, No. 7
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Exclusive and Persistent Use of the Entry Coreceptor CXCR4 by Human Immunodeficiency Virus Type 1 from a Subject Homozygous for CCR5 Delta 32

Nelson L. Michael,1 Julie A. E. Nelson,2 Vineet N. KewalRamani,3 George Chang,4 Stephen J. O'Brien,5 John R. Mascola,1,6 Barbara Volsky,3 Mark Louder,4 Gilbert C. White II,7 Dan R. Littman,3,8 Ronald Swanstrom,2,9 and Thomas R. O'Brien10,*

Division of Retrovirology, Walter Reed Army Institute of Research,1 The Henry M. Jackson Foundation for the Advancement of Military Medicine,4 and Laboratory of Genomic Diversity5 and Viral Epidemiology Branch,10 National Cancer Institute, Rockville, and Department of Infectious Diseases, Naval Medical Research Institute, Bethesda,6 Maryland; Lineberger Comprehensive Cancer Center,2 Division of Hematology and Oncology,7 and Department of Biochemistry and Biophysics,9 University of North Carolina, Chapel Hill, North Carolina; and Skirball Institute3 and Howard Hughes Medical Institute,8 New York University Medical Center, New York, New York

Received 19 November 1997/Accepted 24 March 1998

Individuals who are homozygous for the 32-bp deletion in the gene coding for the chemokine receptor and major human immunodeficiency virus type 1 (HIV-1) coreceptor CCR5 (CCR5 -/-) lack functional cell surface CCR5 molecules and are relatively resistant to HIV-1 infection. HIV-1 infection in CCR5 -/- individuals, although rare, has been increasingly documented. We now report that the viral quasispecies from one such individual throughout disease is homogenous, T cell line tropic, and phenotypically syncytium inducing (SI); exclusively uses CXCR4; and replicates well in CCR5 -/- primary T cells. The recently discovered coreceptors BOB and Bonzo are not used. Although early and persistent SI variants have been described in longitudinal studies, this is the first demonstration of exclusive and persistent CXCR4 usage. With the caveat that the earliest viruses available from this subject were from approximately 4 years following primary infection, these data suggest that HIV-1 infection can be mediated and persistently maintained by viruses which exclusively utilize CXCR4. The lack of evolution toward the available minor coreceptors in this subject underscores the dominant biological roles of the major coreceptors CCR5 and CXCR4. This and two similar subjects (R. Biti, R. Ffrench, J. Young, B. Bennetts, G. Stewart, and T. Liang, Nat. Med. 3:252-253, 1997; I. Theodoreu, L. Meyer, M. Magierowska, C. Katlama, and C. Rouzioux, Lancet 349:1219-1220, 1997) showed relatively rapid CD4+ T-cell declines despite average or low initial viral RNA load. Since viruses which use CXCR4 exclusively cannot infect macrophages, these data have implications for the relative infection of the T-cell compartment versus the macrophage compartment in vivo and for the development of CCR5-based therapeutics.

* Corresponding author. Mailing address: Viral Epidemiology Branch, National Cancer Institute, National Institutes of Health, EPN 434, 6130 Executive Blvd., Rockville, MD 20852. Phone: (301) 496-8115. Fax: (301) 402-0817. E-mail: obrient{at}epndce.nci.nih.gov.

J Virol, July 1998, p. 6040-6047, Vol. 72, No. 7
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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