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Journal of Virology, November 2005, p. 13250-13261, Vol. 79, No. 21
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.21.13250-13261.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Complex Determinants in Human Immunodeficiency Virus Type 1 Envelope gp120 Mediate CXCR4-Dependent Infection of Macrophages

Guity Ghaffari,1,{dagger} Daniel L. Tuttle,2,{dagger} Daniel Briggs,1 Brant R. Burkhardt,2,§ Deepa Bhatt,2 Warren A. Andiman,3 John W. Sleasman,4 and Maureen M. Goodenow1,2,5*

Department of Pediatrics, Division of Immunology, Rheumatology, and Infectious Diseases,1 Department of Pathology, Immunology, and Laboratory Medicine,2 University of Florida Shands Cancer Center, University of Florida, Gainesville, Florida,5 Department of Pediatrics, Division of Infectious Diseases, Yale University, New Haven, Connecticut,3 Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, University of South Florida and All Children's Hospital, St. Petersburg, Florida4

Received 31 March 2005/ Accepted 8 August 2005

Host cell range, or tropism, combined with coreceptor usage defines viral phenotypes as macrophage tropic using CCR5 (M-R5), T-cell-line tropic using CXCR4 (T-X4), or dually lymphocyte and macrophage tropic using CXCR4 alone or in combination with CCR5 (D-X4 or D-R5X4). Although envelope gp120 V3 is necessary and sufficient for M-R5 and T-X4 phenotypes, the clarity of V3 as a dominant phenotypic determinant diminishes in the case of dualtropic viruses. We evaluated D-X4 phenotype, pathogenesis, and emergence of D-X4 viruses in vivo and mapped genetic determinants in gp120 that mediate use of CXCR4 on macrophages ex vivo. Viral quasispecies with D-X4 phenotypes were associated significantly with advanced CD4+-T-cell attrition and commingled with M-R5 or T-X4 viruses in postmortem thymic tissue and peripheral blood. A D-X4 phenotype required complex discontinuous genetic determinants in gp120, including charged and uncharged amino acids in V3, the V5 hypervariable domain, and novel V1/V2 regions distinct from prototypic M-R5 or T-X4 viruses. The D-X4 phenotype was associated with efficient use of CXCR4 and CD4 for fusion and entry but unrelated to levels of virion-associated gp120, indicating that gp120 conformation contributes to cell-specific tropism. The D-X4 phenotype describes a complex and heterogeneous class of envelopes that accumulate multiple amino acid changes along an evolutionary continuum. Unique gp120 determinants required for the use of CXCR4 on macrophages, in contrast to cells of lymphocytic lineage, can provide targets for development of novel strategies to block emergence of X4 quasispecies of human immunodeficiency virus type 1.

* Corresponding author. Mailing address: Department of Pathology, Immunology, & Laboratory Medicine, University of Florida College of Medicine, 1600 SW Archer Road, Gainesville, FL 32610. Phone: (352) 392-3429. Fax: (352) 392-0481. E-mail: goodenow{at}ufl.edu.

{dagger} These authors contributed equally to the research and the manuscript.

Present address: Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, 1600 SW Archer Road, Gainesville, FL 32610.

{ddagger} Present address: Department of Anesthesiology, Box 3094, Duke University Medical Center, Durham, NC 27710.

§ Present address: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, 803D North ARC, 3516 Civic Center Blvd., Philadelphia, PA 19104-4318.

Journal of Virology, November 2005, p. 13250-13261, Vol. 79, No. 21
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.21.13250-13261.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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