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 Pastore, C.
Right arrow Articles by Mosier, D. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pastore, C.
Right arrow Articles by Mosier, D. E.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, February 2003, p. 509-517, Vol. 47, No. 2
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.2.509-517.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Two Mechanisms for Human Immunodeficiency Virus Type 1 Inhibition by N-Terminal Modifications of RANTES{dagger}

Cristina Pastore,1 Gastón R. Picchio,1 Francesco Galimi,2,{ddagger} Richard Fish,3 Oliver Hartley,3 Robin E. Offord,3 and Donald E. Mosier1*

Department of Immunology, The Scripps Research Institute,1 The Salk Institute for Biological Studies, La Jolla, California,2 Département de Biochimie Médicale, Centre Medical Universitaire, Geneva, Switzerland3

Received 14 August 2002/ Returned for modification 24 October 2002/ Accepted 14 November 2002

C-C chemokine receptor 5 (CCR5) is the primary coreceptor for human immunodeficiency virus type 1 (HIV-1) infection. Native chemokines that bind to CCR5 inhibit HIV-1 infection, albeit weakly, but chemically modified chemokines inhibit infection more efficiently. We have investigated the inhibitory mechanism of three N-terminally modified RANTES variants (AOP-, NNY-, and PSC-RANTES) with the MT-2 human T-cell line stably expressing either native or mutated CCR5. The RANTES analogues showed the same rank order (PSC > NNY > AOP) in their capacity to induce prolonged CCR5 internalization, inhibit surface reexpression, and prevent HIV-1 infection on MT-2 cells expressing wild-type CCR5 or CCR5 with four C-terminal serine phosphorylation sites mutated to alanine. None of the RANTES analogues caused internalization of a C-terminal cytoplasmic domain deletion mutant of CCR5, and each derivative had equal potency in inhibiting HIV-1 infection of MT-2 cells expressing this mutant. We conclude that the C-terminal cytoplasmic residues of CCR5 are necessary for receptor sequestration by RANTES analogues but that the process and the relative activity of each derivative are not dependent upon phosphorylation of the C-terminal serine residues. Two mechanisms of antiviral activity are demonstrated: receptor blockade and receptor sequestration. Potency correlates with the ability to induce CCR5 sequestration but not with receptor binding, suggesting that sequestration may make the greater contribution to antiviral activity.

* Corresponding author. Mailing address: Department of Immunology-IMM7, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. Phone: (858) 784-9121. Fax: (858) 784-9190. E-mail: dmosier{at}scripps.edu.

{dagger} Publication 15032-IMM from the Scripps Research Institute.

{ddagger} Permanent address: Department of Biomedical Sciences, University of Sassari Medical School, Sassari 07100, Italy.

Antimicrobial Agents and Chemotherapy, February 2003, p. 509-517, Vol. 47, No. 2
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.2.509-517.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Etemad, B., Fellows, A., Kwambana, B., Kamat, A., Feng, Y., Lee, S., Sagar, M. (2009). Human Immunodeficiency Virus Type 1 V1-to-V5 Envelope Variants from the Chronic Phase of Infection Use CCR5 and Fuse More Efficiently than Those from Early after Infection. J. Virol. 83: 9694-9708 [Abstract] [Full Text]  
  • Dudley, D. M., Wentzel, J. L., Lalonde, M. S., Veazey, R. S., Arts, E. J. (2009). Selection of a Simian-Human Immunodeficiency Virus Strain Resistant to a Vaginal Microbicide in Macaques. J. Virol. 83: 5067-5076 [Abstract] [Full Text]  
  • Muniz-Medina, V. M., Jones, S., Maglich, J. M., Galardi, C., Hollingsworth, R. E., Kazmierski, W. M., Ferris, R. G., Edelstein, M. P., Chiswell, K. E., Kenakin, T. P. (2009). The Relative Activity of "Function Sparing" HIV-1 Entry Inhibitors on Viral Entry and CCR5 Internalization: Is Allosteric Functional Selectivity a Valuable Therapeutic Property?. Mol. Pharmacol. 75: 490-501 [Abstract] [Full Text]  
  • Coetzer, M., Nedellec, R., Salkowitz, J., McLaughlin, S., Liu, Y., Heath, L., Mullins, J. I., Mosier, D. E. (2008). Evolution of CCR5 Use before and during Coreceptor Switching. J. Virol. 82: 11758-11766 [Abstract] [Full Text]  
  • Gaertner, H., Cerini, F., Escola, J.-M., Kuenzi, G., Melotti, A., Offord, R., Rossitto-Borlat, I., Nedellec, R., Salkowitz, J., Gorochov, G., Mosier, D., Hartley, O. (2008). Highly potent, fully recombinant anti-HIV chemokines: Reengineering a low-cost microbicide. Proc. Natl. Acad. Sci. USA 105: 17706-17711 [Abstract] [Full Text]  
  • Tsibris, A. M. N., Sagar, M., Gulick, R. M., Su, Z., Hughes, M., Greaves, W., Subramanian, M., Flexner, C., Giguel, F., Leopold, K. E., Coakley, E., Kuritzkes, D. R. (2008). In Vivo Emergence of Vicriviroc Resistance in a Human Immunodeficiency Virus Type 1 Subtype C-Infected Subject. J. Virol. 82: 8210-8214 [Abstract] [Full Text]  
  • Narazaki, M., Segarra, M., Tosato, G. (2008). Sulfated polysaccharides identified as inducers of neuropilin-1 internalization and functional inhibition of VEGF165 and semaphorin3A. Blood 111: 4126-4136 [Abstract] [Full Text]  
  • Gaertner, H., Lebeau, O., Borlat, I., Cerini, F., Dufour, B., Kuenzi, G., Melotti, A., Fish, R. J., Offord, R., Springael, J.-Y., Parmentier, M., Hartley, O. (2008). Highly potent HIV inhibition: engineering a key anti-HIV structure from PSC-RANTES into MIP-1{beta}/CCL4. Protein Eng Des Sel 21: 65-72 [Abstract] [Full Text]  
  • Pastore, C., Nedellec, R., Ramos, A., Hartley, O., Miamidian, J. L., Reeves, J. D., Mosier, D. E. (2007). Conserved Changes in Envelope Function during Human Immunodeficiency Virus Type 1 Coreceptor Switching. J. Virol. 81: 8165-8179 [Abstract] [Full Text]  
  • Lobritz, M. A., Marozsan, A. J., Troyer, R. M., Arts, E. J. (2007). Natural Variation in the V3 Crown of Human Immunodeficiency Virus Type 1 Affects Replicative Fitness and Entry Inhibitor Sensitivity. J. Virol. 81: 8258-8269 [Abstract] [Full Text]  
  • Kiselyeva, Y., Nedellec, R., Ramos, A., Pastore, C., Margolis, L. B., Mosier, D. E. (2007). Evolution of CXCR4-Using Human Immunodeficiency Virus Type 1 SF162 Is Associated with Two Unique Envelope Mutations. J. Virol. 81: 3657-3661 [Abstract] [Full Text]  
  • Saita, Y., Kodama, E., Orita, M., Kondo, M., Miyazaki, T., Sudo, K., Kajiwara, K., Matsuoka, M., Shimizu, Y. (2006). Structural Basis for the Interaction of CCR5 with a Small Molecule, Functionally Selective CCR5 Agonist.. J. Immunol. 177: 3116-3122 [Abstract] [Full Text]  
  • Lim, J. K., Burns, J. M., Lu, W., DeVico, A. L. (2005). Multiple pathways of amino terminal processing produce two truncated variants of RANTES/CCL5. J. Leukoc. Biol. 78: 442-452 [Abstract] [Full Text]  
  • Hartley, O., Gaertner, H., Wilken, J., Thompson, D., Fish, R., Ramos, A., Pastore, C., Dufour, B., Cerini, F., Melotti, A., Heveker, N., Picard, L., Alizon, M., Mosier, D., Kent, S., Offord, R. (2004). Medicinal chemistry applied to a synthetic protein: Development of highly potent HIV entry inhibitors. Proc. Natl. Acad. Sci. USA 101: 16460-16465 [Abstract] [Full Text]  
  • Lederman, M. M., Veazey, R. S., Offord, R., Mosier, D. E., Dufour, J., Mefford, M., Piatak, M. Jr., Lifson, J. D., Salkowitz, J. R., Rodriguez, B., Blauvelt, A., Hartley, O. (2004). Prevention of Vaginal SHIV Transmission in Rhesus Macaques Through Inhibition of CCR5. Science 306: 485-487 [Abstract] [Full Text]  
  • Pastore, C., Ramos, A., Mosier, D. E. (2004). Intrinsic Obstacles to Human Immunodeficiency Virus Type 1 Coreceptor Switching. J. Virol. 78: 7565-7574 [Abstract] [Full Text]  
  • Kawamura, T., Bruce, S. E., Abraha, A., Sugaya, M., Hartley, O., Offord, R. E., Arts, E. J., Zimmerman, P. A., Blauvelt, A. (2004). PSC-RANTES Blocks R5 Human Immunodeficiency Virus Infection of Langerhans Cells Isolated from Individuals with a Variety of CCR5 Diplotypes. J. Virol. 78: 7602-7609 [Abstract] [Full Text]  
  • Gross, E., Amella, C. A., Pompucci, L., Franchin, G., Sherry, B., Schmidtmayerova, H. (2003). Macrophages and lymphocytes differentially modulate the ability of RANTES to inhibit HIV-1 infection. J. Leukoc. Biol. 74: 781-790 [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»