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J Virol, March 1998, p. 2509-2515, Vol. 72, No. 3
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Identification of Determinants on a Dualtropic Human Immunodeficiency Virus Type 1 Envelope Glycoprotein That Confer Usage of CXCR4

Michael W. Cho,1,* Myung K. Lee,1 Michelle C. Carney,1 Joanne F. Berson,2 Robert W. Doms,2 and Malcolm A. Martin1

Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-0460,1 and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 191042

Received 7 August 1997/Accepted 5 December 1997

The chemokine receptors CCR5 and CXCR4, in combination with CD4, mediate cellular entry of macrophage-tropic (M-tropic) and T-cell-tropic strains of human immunodeficiency virus type 1 (HIV-1), respectively, while dualtropic viruses can use either receptor. We have constructed a panel of chimeric viruses and envelope glycoproteins in which various domains of the dualtropic HIV-1DH12 gp160 were introduced into the genetic background of an M-tropic HIV-1 isolate, HIV-1AD8. These constructs were employed in cell fusion and virus infectivity assays using peripheral blood mononuclear cells, MT4 T cells, primary monocyte-derived macrophages, or HOS-CD4 cell lines, expressing various chemokine receptors, to assess the contributions of different gp120 subdomains in coreceptor usage and cellular tropism. As expected, the dualtropic HIV-1DH12 gp120 utilized either CCR3, CCR5, or CXCR4, whereas HIV-1AD8 gp120 was able to use only CCR3 or CCR5. We found that either the V1/V2 or the V3 region of HIV-1DH12 gp120 individually conferred on HIV-1AD8 the ability to use CXCR4, while the combination of both the V1/V2 and V3 regions increased the efficiency of CXCR4 use. In addition, while the V4 or the V5 region of HIV-1DH12 gp120 failed to confer the capacity to utilize CXCR4 on HIV-1AD8, these regions were required in conjunction with regions V1 to V3 of HIV-1DH12 gp120 for efficient utilization of CXCR4. Comparison of virus infectivity analyses with various cell types and cell fusion assays revealed assay-dependent discrepancies and indicated that events occurring at the cell surface during infection are complex and cannot always be predicted by any one assay.

* Corresponding author. Mailing address: Laboratory of Molecular Microbiology, NIH, NIAID, 9000 Rockville Pike, Bldg. 4, Rm. 339, Bethesda, MD 20892-0460. Phone: (301) 496-0576. Fax: (301) 402-0226. E-mail: MCho{at}nih.gov.




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