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 Schols, D.
Right arrow Articles by De Clercq, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Schols, D.
Right arrow Articles by De Clercq, E.

 Previous Article  |  Next Article 

J Virol, May 1998, p. 4032-4037, Vol. 72, No. 5
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

T-Cell-Line-Tropic Human Immunodeficiency Virus Type 1 That Is Made Resistant to Stromal Cell-Derived Factor 1alpha Contains Mutations in the Envelope gp120 but Does Not Show a Switch in Coreceptor Use

Dominique Schols,1,* José A. Esté,1,2 Cecilia Cabrera,2 and Erik De Clercq1

Laboratory of Experimental Chemotherapy, Rega Institute for Medical Research, B-3000 Leuven, Belgium,1 and Institut de la Recerca de la SIDA Caixa, Hospital Universitari Germans Trias i Pujol, Badalona, Spain2

Received 27 October 1997/Accepted 2 February 1998

The NL4.3 T-cell-line-tropic human immunodeficiency virus type 1 strain is sensitive to the CXC chemokine stromal cell-derived factor 1alpha (SDF-1alpha ), the natural ligand for CXC chemokine receptor 4 (CXCR4); the 50% inhibitory concentration (IC50) in MT-4 cells is 130 ng/ml. We generated resistant virus through passaging of the virus in the presence of increasing concentrations of SDF-1alpha . After 24 passages, the virus was no longer sensitive to SDF-1alpha (SDF-1alpha res virus) (IC50, >2 µg/ml) and became resistant to SDF-1beta (IC50, >2 µg/ml) and to a specific CXCR4 monoclonal antibody (IC50, >20 µg/ml). The SDF-1alpha res virus was about 10-fold less sensitive than the wild-type virus to the bicyclam AMD3100, a specific CXCR4 antagonist. The SDF-1alpha res virus contained the following mutations in the gp120 molecule: N106K in the V1 loop; S134N and F145L in the V2 loop; F245I in the C2 loop; K269E, Q278H, I288V, and N293D in the V3 loop; a deletion of 5 amino acids (FNSTW) at positions 364 to 368 in the V4 loop; and R378T in the CD4 binding domain. Replication of the NL4.3 wild-type virus and the SDF-1alpha res virus was demonstrated in U87 cells that coexpressed CD4 and CXCR4 (U87.CD4.CXCR4) but not in U87.CD4.CCR5 cells. Thus, the resistant virus was not able to switch to the CC chemokine receptor 5 (CCR5) coreceptor (the main coreceptor for macrophage-tropic viruses). The SDF-1alpha res virus replicated in HOS.CD4 cells expressing CCR1, CCR2b, CCR3, CCR4, CCR5, and CXCR4 but also in HOS.CD4.pBABE cells. However, all HOS transfectant cells expressed a low level of CXCR4. Neither of the two virus strains was able to infect HOS.CXCR4 or HOS.CCR5 transfectants, demonstrating the necessity of the CD4 receptor. The T-cell-line-tropic SDF-1alpha res virus was thus able to overcome the inhibitory effect of SDF-1alpha through mutations in gp120 but still needed CXCR4 to enter the cells.

* Corresponding author. Mailing address: Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium. Phone: 32-16-33-73-41. Fax: 32-16-33-73-40. E-mail: dominique.schols{at}rega.kuleuven.ac.be.

J Virol, May 1998, p. 4032-4037, Vol. 72, No. 5
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Vermeire, K., Van Laethem, K., Janssens, W., Bell, T. W., Schols, D. (2009). Human Immunodeficiency Virus Type 1 Escape from Cyclotriazadisulfonamide-Induced CD4-Targeted Entry Inhibition Is Associated with Increased Neutralizing Antibody Susceptibility. J. Virol. 83: 9577-9583 [Abstract] [Full Text]  
  • Moncunill, G., Armand-Ugon, M., Clotet-Codina, I., Pauls, E., Ballana, E., Llano, A., Romagnoli, B., Vrijbloed, J. W., Gombert, F. O., Clotet, B., De Marco, S., Este, J. A. (2008). Anti-HIV Activity and Resistance Profile of the CXC Chemokine Receptor 4 Antagonist POL3026. Mol. Pharmacol. 73: 1264-1273 [Abstract] [Full Text]  
  • Lin, G., Bertolotti-Ciarlet, A., Haggarty, B., Romano, J., Nolan, K. M., Leslie, G. J., Jordan, A. P.-O., Huang, C.-c., Kwong, P. D., Doms, R. W., Hoxie, J. A. (2007). Replication-Competent Variants of Human Immunodeficiency Virus Type 2 Lacking the V3 Loop Exhibit Resistance to Chemokine Receptor Antagonists. J. Virol. 81: 9956-9966 [Abstract] [Full Text]  
  • Briz, V., Poveda, E., Soriano, V. (2006). HIV entry inhibitors: mechanisms of action and resistance pathways. J Antimicrob Chemother 57: 619-627 [Abstract] [Full Text]  
  • Blaak, H., Boers, P. H. M., Gruters, R. A., Schuitemaker, H., van der Ende, M. E., Osterhaus, A. D. M. E. (2005). CCR5, GPR15, and CXCR6 Are Major Coreceptors of Human Immunodeficiency Virus Type 2 Variants Isolated from Individuals with and without Plasma Viremia. J. Virol. 79: 1686-1700 [Abstract] [Full Text]  
  • Nameki, D., Kodama, E., Ikeuchi, M., Mabuchi, N., Otaka, A., Tamamura, H., Ohno, M., Fujii, N., Matsuoka, M. (2005). Mutations Conferring Resistance to Human Immunodeficiency Virus Type 1 Fusion Inhibitors Are Restricted by gp41 and Rev-Responsive Element Functions. J. Virol. 79: 764-770 [Abstract] [Full Text]  
  • Princen, K., Hatse, S., Vermeire, K., Aquaro, S., De Clercq, E., Gerlach, L.-O., Rosenkilde, M., Schwartz, T. W., Skerlj, R., Bridger, G., Schols, D. (2004). Inhibition of Human Immunodeficiency Virus Replication by a Dual CCR5/CXCR4 Antagonist. J. Virol. 78: 12996-13006 [Abstract] [Full Text]  
  • Balzarini, J., Hatse, S., Vermeire, K., Princen, K., Aquaro, S., Perno, C.-F., De Clercq, E., Egberink, H., Vanden Mooter, G., Peumans, W., Van Damme, E., Schols, D. (2004). Mannose-Specific Plant Lectins from the Amaryllidaceae Family Qualify as Efficient Microbicides for Prevention of Human Immunodeficiency Virus Infection. Antimicrob. Agents Chemother. 48: 3858-3870 [Abstract] [Full Text]  
  • Kenakin, T. (2004). Allosteric Modulators: The New Generation of Receptor Antagonist. Mol. Interv. 4: 222-229 [Abstract] [Full Text]  
  • Stalmeijer, E. H. B., van Rij, R. P., Boeser-Nunnink, B., Visser, J. A., Naarding, M. A., Schols, D., Schuitemaker, H. (2004). In Vivo Evolution of X4 Human Immunodeficiency Virus Type 1 Variants in the Natural Course of Infection Coincides with Decreasing Sensitivity to CXCR4 Antagonists. J. Virol. 78: 2722-2728 [Abstract] [Full Text]  
  • Kuhmann, S. E., Pugach, P., Kunstman, K. J., Taylor, J., Stanfield, R. L., Snyder, A., Strizki, J. M., Riley, J., Baroudy, B. M., Wilson, I. A., Korber, B. T., Wolinsky, S. M., Moore, J. P. (2004). Genetic and Phenotypic Analyses of Human Immunodeficiency Virus Type 1 Escape from a Small-Molecule CCR5 Inhibitor. J. Virol. 78: 2790-2807 [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]  
  • Moore, J. P., Doms, R. W. (2003). The entry of entry inhibitors: A fusion of science and medicine. Proc. Natl. Acad. Sci. USA 100: 10598-10602 [Abstract] [Full Text]  
  • Gitlin, L., Andino, R. (2003). Nucleic Acid-Based Immune System: the Antiviral Potential of Mammalian RNA Silencing. J. Virol. 77: 7159-7165 [Full Text]  
  • Ichiyama, K., Yokoyama-Kumakura, S., Tanaka, Y., Tanaka, R., Hirose, K., Bannai, K., Edamatsu, T., Yanaka, M., Niitani, Y., Miyano-Kurosaki, N., Takaku, H., Koyanagi, Y., Yamamoto, N. (2003). A duodenally absorbable CXC chemokine receptor 4 antagonist, KRH-1636, exhibits a potent and selective anti-HIV-1 activity. Proc. Natl. Acad. Sci. USA 100: 4185-4190 [Abstract] [Full Text]  
  • Trkola, A., Kuhmann, S. E., Strizki, J. M., Maxwell, E., Ketas, T., Morgan, T., Pugach, P., Xu, S., Wojcik, L., Tagat, J., Palani, A., Shapiro, S., Clader, J. W., McCombie, S., Reyes, G. R., Baroudy, B. M., Moore, J. P. (2002). HIV-1 escape from a small molecule, CCR5-specific entry inhibitor does not involve CXCR4 use. Proc. Natl. Acad. Sci. USA 99: 395-400 [Abstract] [Full Text]  
  • Pontow, S., Ratner, L. (2001). Evidence for Common Structural Determinants of Human Immunodeficiency Virus Type 1 Coreceptor Activity Provided through Functional Analysis of CCR5/CXCR4 Chimeric Coreceptors. J. Virol. 75: 11503-11514 [Abstract] [Full Text]  
  • Dragic, T. (2001). An overview of the determinants of CCR5 and CXCR4 co-receptor function. J. Gen. Virol. 82: 1807-1814 [Full Text]  
  • KENAKIN, T. (2001). Inverse, protean, and ligand-selective agonism: matters of receptor conformation. FASEB J. 15: 598-611 [Abstract] [Full Text]  
  • Witvrouw, M., Fikkert, V., Pluymers, W., Matthews, B., Mardel, K., Schols, D., Raff, J., Debyser, Z., De Clercq, E., Holan, G., Pannecouque, C. (2000). Polyanionic (i.e., Polysulfonate) Dendrimers Can Inhibit the Replication of Human Immunodeficiency Virus by Interfering with Both Virus Adsorption and Later Steps (Reverse Transcriptase/Integrase) in the Virus Replicative Cycle. Mol. Pharmacol. 58: 1100-1108 [Abstract] [Full Text]  
  • Pluymers, W., Neamati, N., Pannecouque, C., Fikkert, V., Marchand, C., Burke, T. R. Jr., Pommier, Y., Schols, D., De Clercq, E., Debyser, Z., Witvrouw, M. (2000). Viral Entry as the Primary Target for the Anti-HIV Activity of Chicoric Acid and Its Tetra-Acetyl Esters. Mol. Pharmacol. 58: 641-648 [Abstract] [Full Text]  
  • Zhang, Y.-j., Lou, B., Lal, R. B., Gettie, A., Marx, P. A., Moore, J. P. (2000). Use of Inhibitors To Evaluate Coreceptor Usage by Simian and Simian/Human Immunodeficiency Viruses and Human Immunodeficiency Virus Type 2 in Primary Cells. J. Virol. 74: 6893-6910 [Abstract] [Full Text]  
  • Torre, V. S., Marozsan, A. J., Albright, J. L., Collins, K. R., Hartley, O., Offord, R. E., Quiñones-Mateu, M. E., Arts, E. J. (2000). Variable Sensitivity of CCR5-Tropic Human Immunodeficiency Virus Type 1 Isolates to Inhibition by RANTES Analogs. J. Virol. 74: 4868-4876 [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]  
  • Maeda, Y., Foda, M., Matsushita, S., Harada, S. (2000). Involvement of both the V2 and V3 Regions of the CCR5-Tropic Human Immunodeficiency Virus Type 1 Envelope in Reduced Sensitivity to Macrophage Inflammatory Protein 1alpha. J. Virol. 74: 1787-1793 [Abstract] [Full Text]  
  • Steinberger, P., Andris-Widhopf, J., Buhler, B., Torbett, B. E., Barbas, C. F. III (2000). Functional deletion of the CCR5 receptor by intracellular immunization produces cells that are refractory to CCR5-dependent HIV-1 infection and cell fusion. Proc. Natl. Acad. Sci. USA 97: 805-810 [Abstract] [Full Text]  
  • Schramm, B., Penn, M. L., Speck, R. F., Chan, S. Y., De Clercq, E., Schols, D., Connor, R. I., Goldsmith, M. A. (2000). Viral Entry through CXCR4 Is a Pathogenic Factor and Therapeutic Target in Human Immunodeficiency Virus Type 1 Disease. J. Virol. 74: 184-192 [Abstract] [Full Text]  
  • Daelemans, D., Schols, D., Witvrouw, M., Pannecouque, C., Hatse, S., van Dooren, S., Hamy, F., Klimkait, T., de Clercq, E., VanDamme, A.-M. (2000). A Second Target for the Peptoid Tat/Transactivation Response Element Inhibitor CGP64222: Inhibition of Human Immunodeficiency Virus Replication by Blocking CXC-Chemokine Receptor 4-Mediated Virus Entry. Mol. Pharmacol. 57: 116-124 [Abstract] [Full Text]  
  • Baba, M., Nishimura, O., Kanzaki, N., Okamoto, M., Sawada, H., Iizawa, Y., Shiraishi, M., Aramaki, Y., Okonogi, K., Ogawa, Y., Meguro, K., Fujino, M. (1999). A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proc. Natl. Acad. Sci. USA 96: 5698-5703 [Abstract] [Full Text]  
  • Zhang, Y.-j., Moore, J. P. (1999). Will Multiple Coreceptors Need To Be Targeted by Inhibitors of Human Immunodeficiency Virus Type 1 Entry?. J. Virol. 73: 3443-3448 [Abstract] [Full Text]  
  • Arakaki, R., Tamamura, H., Premanathan, M., Kanbara, K., Ramanan, S., Mochizuki, K., Baba, M., Fujii, N., Nakashima, H. (1999). T134, a Small-Molecule CXCR4 Inhibitor, Has No Cross-Drug Resistance with AMD3100, a CXCR4 Antagonist with a Different Structure. J. Virol. 73: 1719-1723 [Abstract] [Full Text]  
  • Penn, M. L., Grivel, J.-C., Schramm, B., Goldsmith, M. A., Margolis, L. (1999). CXCR4 utilization is sufficient to trigger CD4+ T cell depletion in HIV-1-infected human lymphoid tissue. Proc. Natl. Acad. Sci. USA 96: 663-668 [Abstract] [Full Text]  
  • Esté, J. A., Cabrera, C., De Clercq, E., Struyf, S., Van Damme, J., Bridger, G., Skerlj, R. T., Abrams, M. J., Henson, G., Gutierrez, A., Clotet, B., Schols, D. (1999). Activity of Different Bicyclam Derivatives against Human Immunodeficiency Virus Depends on Their Interaction with the CXCR4 Chemokine Receptor. Mol. Pharmacol. 55: 67-73 [Abstract] [Full Text]  
  • Lewis, J., Balfe, P., Arnold, C., Kaye, S., Tedder, R. S., McKeating, J. A. (1998). Development of a Neutralizing Antibody Response during Acute Primary Human Immunodeficiency Virus Type 1 Infection and the Emergence of Antigenic Variants. J. Virol. 72: 8943-8951 [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»