This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yi, Y.
Right arrow Articles by Collman, R. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yi, Y.
Right arrow Articles by Collman, R. G.

 Previous Article  |  Next Article 

Journal of Virology, September 1999, p. 7117-7125, Vol. 73, No. 9
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Role of CXCR4 in Cell-Cell Fusion and Infection of Monocyte-Derived Macrophages by Primary Human Immunodeficiency Virus Type 1 (HIV-1) Strains: Two Distinct Mechanisms of HIV-1 Dual Tropism

Yanjie Yi,1 Stuart N. Isaacs,2 Darlisha A. Williams,1 Ian Frank,2 Dominique Schols,3 Erik De Clercq,3 Dennis L. Kolson,4 and Ronald G. Collman1,*

Divisions of Pulmonary and Critical Care1 and Infectious Diseases,2 Departments of Medicine and Neurology,4 University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, and Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium3

Received 2 April 1999/Accepted 20 May 1999

Dual-tropic human immunodeficiency virus type 1 (HIV-1) strains infect both primary macrophages and transformed T-cell lines. Prototype T-cell line-tropic (T-tropic) strains use CXCR4 as their principal entry coreceptor (X4 strains), while macrophagetropic (M-tropic) strains use CCR5 (R5 strains). Prototype dual tropic strains use both coreceptors (R5X4 strains). Recently, CXCR4 expressed on macrophages was found to support infection by certain HIV-1 isolates, including the dual-tropic R5X4 strain 89.6, but not by T-tropic X4 prototypes like 3B. To better understand the cellular basis for dual tropism, we analyzed the macrophage coreceptors used for Env-mediated cell-cell fusion as well as infection by several dual-tropic HIV-1 isolates. Like 89.6, the R5X4 strain DH12 fused with and infected both wild-type and CCR5-negative macrophages. The CXCR4-specific inhibitor AMD3100 blocked DH12 fusion and infection in macrophages that lacked CCR5 but not in wild-type macrophages. This finding indicates two independent entry pathways in macrophages for DH12, CCR5 and CXCR4. Three primary isolates that use CXCR4 but not CCR5 (tybe, UG021, and UG024) replicated efficiently in macrophages regardless of whether CCR5 was present, and AMD3100 blocking of CXCR4 prevented infection in both CCR5 negative and wild-type macrophages. Fusion mediated by UG021 and UG024 Envs in both wild-type and CCR5-deficient macrophages was also blocked by AMD3100. Therefore, these isolates use CXCR4 exclusively for entry into macrophages. These results confirm that macrophage CXCR4 can be used for fusion and infection by primary HIV-1 isolates and indicate that CXCR4 may be the sole macrophage coreceptor for some strains. Thus, dual tropism can result from two distinct mechanisms: utilization of both CCR5 and CXCR4 on macrophages and T-cell lines, respectively (dual-tropic R5X4), or the ability to efficiently utilize CXCR4 on both macrophages and T-cell lines (dual-tropic X4).

* Corresponding author. Mailing address: 522 Johnson Pavilion, University of Pennsylvania School of Medicine, 36th & Hamilton Walk, Philadelphia, PA 19104-6060. Phone: (215) 898-0913. Fax: (215) 573-4446. E-mail: collmanr{at}mail.med.upenn.edu.

Journal of Virology, September 1999, p. 7117-7125, Vol. 73, No. 9
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Gray, L., Roche, M., Churchill, M. J., Sterjovski, J., Ellett, A., Poumbourios, P., Sheffief, S., Wang, B., Saksena, N., Purcell, D. F. J., Wesselingh, S., Cunningham, A. L., Brew, B. J., Gabuzda, D., Gorry, P. R. (2009). Tissue-Specific Sequence Alterations in the Human Immunodeficiency Virus Type 1 Envelope Favoring CCR5 Usage Contribute to Persistence of Dual-Tropic Virus in the Brain. J. Virol. 83: 5430-5441 [Abstract] [Full Text]  
  • Harrison, J. E., Lynch, J. B., Sierra, L.-J., Blackburn, L. A., Ray, N., Collman, R. G., Doms, R. W. (2008). Baseline Resistance of Primary Human Immunodeficiency Virus Type 1 Strains to the CXCR4 Inhibitor AMD3100. J. Virol. 82: 11695-11704 [Abstract] [Full Text]  
  • Goodenow, M. M., Collman, R. G. (2006). HIV-1 coreceptor preference is distinct from target cell tropism: a dual-parameter nomenclature to define viral phenotypes. J. Leukoc. Biol. 80: 965-972 [Abstract] [Full Text]  
  • Gray, L., Churchill, M. J., Keane, N., Sterjovski, J., Ellett, A. M., Purcell, D. F. J., Poumbourios, P., Kol, C., Wang, B., Saksena, N. K., Wesselingh, S. L., Price, P., French, M., Gabuzda, D., Gorry, P. R. (2006). Genetic and Functional Analysis of R5X4 Human Immunodeficiency Virus Type 1 Envelope Glycoproteins Derived from Two Individuals Homozygous for the CCR5{Delta}32 Allele.. J. Virol. 80: 3684-3691 [Abstract] [Full Text]  
  • Ghaffari, G., Tuttle, D. L., Briggs, D., Burkhardt, B. R., Bhatt, D., Andiman, W. A., Sleasman, J. W., Goodenow, M. M. (2005). Complex Determinants in Human Immunodeficiency Virus Type 1 Envelope gp120 Mediate CXCR4-Dependent Infection of Macrophages. J. Virol. 79: 13250-13261 [Abstract] [Full Text]  
  • Jayakumar, P., Berger, I., Autschbach, F., Weinstein, M., Funke, B., Verdin, E., Goldsmith, M. A., Keppler, O. T. (2005). Tissue-Resident Macrophages Are Productively Infected Ex Vivo by Primary X4 Isolates of Human Immunodeficiency Virus Type 1. J. Virol. 79: 5220-5226 [Abstract] [Full Text]  
  • Yi, Y., Shaheen, F., Collman, R. G. (2005). Preferential Use of CXCR4 by R5X4 Human Immunodeficiency Virus Type 1 Isolates for Infection of Primary Lymphocytes. J. Virol. 79: 1480-1486 [Abstract] [Full Text]  
  • Hoshino, Y., Tse, D. B., Rochford, G., Prabhakar, S., Hoshino, S., Chitkara, N., Kuwabara, K., Ching, E., Raju, B., Gold, J. A., Borkowsky, W., Rom, W. N., Pine, R., Weiden, M. (2004). Mycobacterium tuberculosis-Induced CXCR4 and Chemokine Expression Leads to Preferential X4 HIV-1 Replication in Human Macrophages. J. Immunol. 172: 6251-6258 [Abstract] [Full Text]  
  • Devine, S. M., Flomenberg, N., Vesole, D. H., Liesveld, J., Weisdorf, D., Badel, K., Calandra, G., DiPersio, J. F. (2004). Rapid Mobilization of CD34+ Cells Following Administration of the CXCR4 Antagonist AMD3100 to Patients With Multiple Myeloma and Non-Hodgkin's Lymphoma. JCO 22: 1095-1102 [Abstract] [Full Text]  
  • Igarashi, T., Donau, O. K., Imamichi, H., Dumaurier, M.-J., Sadjadpour, R., Plishka, R. J., Buckler-White, A., Buckler, C., Suffredini, A. F., Lane, H. C., Moore, J. P., Martin, M. A. (2003). Macrophage-Tropic Simian/Human Immunodeficiency Virus Chimeras Use CXCR4, Not CCR5, for Infections of Rhesus Macaque Peripheral Blood Mononuclear Cells and Alveolar Macrophages. J. Virol. 77: 13042-13052 [Abstract] [Full Text]  
  • Igarashi, T., Imamichi, H., Brown, C. R., Hirsch, V. M., Martin, M. A. (2003). The emergence and characterization of macrophage-tropic SIV/HIV chimeric viruses (SHIVs) present in CD4+ T cell-depleted rhesus monkeys. J. Leukoc. Biol. 74: 772-780 [Abstract] [Full Text]  
  • Lee, C., Liu, Q.-H., Tomkowicz, B., Yi, Y., Freedman, B. D., Collman, R. G. (2003). Macrophage activation through CCR5- and CXCR4-mediated gp120-elicited signaling pathways. J. Leukoc. Biol. 74: 676-682 [Abstract] [Full Text]  
  • Vermeire, K., Schols, D. (2003). Specific CD4 down-modulating compounds with potent anti-HIV activity. J. Leukoc. Biol. 74: 667-675 [Abstract] [Full Text]  
  • von Lindern, J. J., Rojo, D., Grovit-Ferbas, K., Yeramian, C., Deng, C., Herbein, G., Ferguson, M. R., Pappas, T. C., Decker, J. M., Singh, A., Collman, R. G., O'Brien, W. A. (2003). Potential Role for CD63 in CCR5-Mediated Human Immunodeficiency Virus Type 1 Infection of Macrophages. J. Virol. 77: 3624-3633 [Abstract] [Full Text]  
  • Del Corno, M., Liu, Q.-H., Schols, D., de Clercq, E., Gessani, S., Freedman, B. D., Collman, R. G. (2001). HIV-1 gp120 and chemokine activation of Pyk2 and mitogen-activated protein kinases in primary macrophages mediated by calcium-dependent, pertussis toxin-insensitive chemokine receptor signaling. Blood 98: 2909-2916 [Abstract] [Full Text]  
  • Miller, E. D., Duus, K. M., Townsend, M., Yi, Y., Collman, R., Reitz, M., Su, L. (2001). Human Immunodeficiency Virus Type 1 IIIB Selected for Replication In Vivo Exhibits Increased Envelope Glycoproteins in Virions without Alteration in Coreceptor Usage: Separation of In Vivo Replication from Macrophage Tropism. J. Virol. 75: 8498-8506 [Abstract] [Full Text]  
  • Tokunaga, K., Greenberg, M. L., Morse, M. A., Cumming, R. I., Lyerly, H. K., Cullen, B. R. (2001). Molecular Basis for Cell Tropism of CXCR4-Dependent Human Immunodeficiency Virus Type 1 Isolates. J. Virol. 75: 6776-6785 [Abstract] [Full Text]  
  • Neil, S., Martin, F., Ikeda, Y., Collins, M. (2001). Postentry Restriction to Human Immunodeficiency Virus-Based Vector Transduction in Human Monocytes. J. Virol. 75: 5448-5456 [Abstract] [Full Text]  
  • Lai, J.-P., Ho, W.-Z., Zhan, G.-X., Yi, Y., Collman, R. G., Douglas, S. D. (2001). Substance P antagonist (CP-96,345) inhibits HIV-1 replication in human mononuclear phagocytes. Proc. Natl. Acad. Sci. USA 98: 3970-3975 [Abstract] [Full Text]  
  • Kim, S. S., You, X. J., Harmon, M.-E., Overbaugh, J., Fan, H. (2001). Use of Helper-Free Replication-Defective Simian Immunodeficiency Virus-Based Vectors To Study Macrophage and T Tropism: Evidence for Distinct Levels of Restriction in Primary Macrophages and a T-Cell Line. J. Virol. 75: 2288-2300 [Abstract] [Full Text]  
  • Collman, R. G., Yi, Y., Liu, Q.-H., Freedman, B. D. (2000). Chemokine signaling and HIV-1 fusion mediated by macrophage CXCR4: implications for target cell tropism. J. Leukoc. Biol. 68: 318-323 [Abstract] [Full Text]  
  • Lathey, J. L., Brambilla, D., Goodenow, M. M., Nokta, M., Rasheed, S., Siwak, E. B., Bremer, J. W., Huang, D. D., Yi, Y., Reichelderfer, P. S., Collman, R. G. (2000). Co-receptor usage was more predictive than NSI/SI phenotype for HIV replication in macrophages: is NSI/SI phenotyping sufficient?. J. Leukoc. Biol. 68: 324-330 [Abstract] [Full Text]  
  • Lee, S., Tiffany, H. L., King, L., Murphy, P. M., Golding, H., Zaitseva, M. B. (2000). CCR8 on Human Thymocytes Functions as a Human Immunodeficiency Virus Type 1 Coreceptor. J. Virol. 74: 6946-6952 [Abstract] [Full Text]  
  • Sharron, M., Pohlmann, S., Price, K., Lolis, E., Tsang, M., Kirchhoff, F., Doms, R. W., Lee, B. (2000). Expression and coreceptor activity of STRL33/Bonzo on primary peripheral blood lymphocytes. Blood 96: 41-49 [Abstract] [Full Text]  
  • Lee, S., Lapham, C. K., Chen, H., King, L., Manischewitz, J., Romantseva, T., Mostowski, H., Stantchev, T. S., Broder, C. C., Golding, H. (2000). Coreceptor Competition for Association with CD4 May Change the Susceptibility of Human Cells to Infection with T-Tropic and Macrophagetropic Isolates of Human Immunodeficiency Virus Type 1. J. Virol. 74: 5016-5023 [Abstract] [Full Text]  
  • De Clercq, E. (2000). Inhibition of HIV Infection by Bicyclams, Highly Potent and Specific CXCR4 Antagonists. Mol. Pharmacol. 57: 833-839 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»