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Journal of Virology, April 2002, p. 3114-3124, Vol. 76, No. 7
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.7.3114-3124.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

A Human Immunodeficiency Virus Type 1 Isolate from an Infected Person Homozygous for CCR5{Delta}32 Exhibits Dual Tropism by Infecting Macrophages and MT2 Cells via CXCR4

Hassan M. Naif,1* Anthony L. Cunningham,1 Mohammed Alali,1 Shan Li,1 Najla Nasr,1 Marc M. Buhler,2 Dominique Schols,3 Erik de Clercq,3 and Graeme Stewart2

Centre for Virus Research,1 Institute of Immunology and Allergy Research, The Westmead Millennium Institute, The University of Sydney, Sydney, New South Wales, Australia,2 Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium3

Received 20 August 2001/ Accepted 17 December 2001

The mechanisms of human immunodeficiency virus (HIV) infection of a man (VH) homozygous for the CCR5{Delta}32 mutation were investigated, and coreceptors other than CCR5 used by HIV type 1 (HIV-1) isolated from this individual were identified. In contrast to previous reports, this individual's rate of disease progression was not accelerated. Homozygosity for CCR5{Delta}32 mutation was demonstrated by PCR and DNA sequencing (R. Biti et al., Nat. Med. 3:252-253, 1997). CCR5 surface expression was absent on T lymphocytes and macrophages. HIV was isolated by coculture with peripheral blood mononuclear cells (PBMCs) from siblings who were homozygous (VM) or wild type (WT) for the CCR5{Delta}32 mutation. The virus demonstrated dual tropism for infection of MT2 cell line and primary macrophages. Sequencing of the full HIV genome directly from the patient's PBMCs revealed 21 nucleotide insertions in the V1 region of gp120. The VH envelope sequence segregated apart from both the T-cell-line-adapted tropic strains NL4-3 and SF2 and M-tropic strain JRFL or YU2 by phylogenetic tree analysis. VH was shown to utilize predominantly CXCR4 for entry into T lymphocytes and macrophages by HOS.CD4 cell infection assay, direct envelope protein fusion, and inhibition by anti-CXCR4 monoclonal antibody (12G5), SDF-1, and AMD3100. Microsatellite mapping demonstrated the separate inheritance of CXCR4 by both homozygote brothers (VH and VM). Our study demonstrates the ability of certain strains of HIV to readily use CXCR4 for infection or entry into macrophages, which is highly relevant to the pathogenesis of late-stage disease and presumably also HIV transmission.

* Corresponding author. Mailing address: Molecular Pathogenesis Laboratory, Centre for Virus Research, Westmead Millennium Institute, The University of Sydney, Westmead, NSW 2145, Australia. Phone: (61-2) 9845-9118. Fax: (61-2) 9845-9100. E-mail: hassan_naif{at}wmi.usyd.edu.au.

Journal of Virology, April 2002, p. 3114-3124, Vol. 76, No. 7
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.7.3114-3124.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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