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Use of a Small Molecule CCR5 Inhibitor in Macaques to Treat Simian Immunodeficiency Virus Infection or Prevent Simian–Human Immunodeficiency Virus Infection
Human immunodeficiency virus type 1 (HIV-1) fuses with cells after sequential interactions between its envelope glycoproteins, CD4 and a coreceptor, usually CC chemokine receptor 5 (CCR5) or CXC receptor 4 (CXCR4). CMPD 167 is a CCR5-specific small molecule with potent antiviral activity in vitro. W...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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The Rockefeller University Press
2003
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2194125/ https://www.ncbi.nlm.nih.gov/pubmed/14623909 http://dx.doi.org/10.1084/jem.20031266 |
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author | Veazey, Ronald S. Klasse, Per Johan Ketas, Thomas J. Reeves, Jacqueline D. Piatak, Michael Kunstman, Kevin Kuhmann, Shawn E. Marx, Preston A. Lifson, Jeffrey D. Dufour, Jason Mefford, Megan Pandrea, Ivona Wolinsky, Steven M. Doms, Robert W. DeMartino, Julie A. Siciliano, Salvatore J. Lyons, Kathy Springer, Martin S. Moore, John P. |
author_facet | Veazey, Ronald S. Klasse, Per Johan Ketas, Thomas J. Reeves, Jacqueline D. Piatak, Michael Kunstman, Kevin Kuhmann, Shawn E. Marx, Preston A. Lifson, Jeffrey D. Dufour, Jason Mefford, Megan Pandrea, Ivona Wolinsky, Steven M. Doms, Robert W. DeMartino, Julie A. Siciliano, Salvatore J. Lyons, Kathy Springer, Martin S. Moore, John P. |
author_sort | Veazey, Ronald S. |
collection | PubMed |
description | Human immunodeficiency virus type 1 (HIV-1) fuses with cells after sequential interactions between its envelope glycoproteins, CD4 and a coreceptor, usually CC chemokine receptor 5 (CCR5) or CXC receptor 4 (CXCR4). CMPD 167 is a CCR5-specific small molecule with potent antiviral activity in vitro. We show that CMPD 167 caused a rapid and substantial (4–200-fold) decrease in plasma viremia in six rhesus macaques chronically infected with simian immunodeficiency virus (SIV) strains SIVmac251 or SIVB670, but not in an animal infected with the X4 simian–human immunodeficiency virus (SHIV), SHIV-89.6P. In three of the SIV-infected animals, viremia reduction was sustained. In one, there was a rapid, but partial, rebound and in another, there was a rapid and complete rebound. There was a substantial delay (>21 d) between the end of therapy and the onset of full viremia rebound in two animals. We also evaluated whether vaginal administration of gel-formulated CMPD 167 could prevent vaginal transmission of the R5 virus, SHIV-162P4. Complete protection occurred in only 2 of 11 animals, but early viral replication was significantly less in the 11 CMPD 167-recipients than in 9 controls receiving carrier gel. These findings support the development of small molecule CCR5 inhibitors as antiviral therapies, and possibly as components of a topical microbicide to prevent HIV-1 sexual transmission. |
format | Text |
id | pubmed-2194125 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2003 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-21941252008-04-22 Use of a Small Molecule CCR5 Inhibitor in Macaques to Treat Simian Immunodeficiency Virus Infection or Prevent Simian–Human Immunodeficiency Virus Infection Veazey, Ronald S. Klasse, Per Johan Ketas, Thomas J. Reeves, Jacqueline D. Piatak, Michael Kunstman, Kevin Kuhmann, Shawn E. Marx, Preston A. Lifson, Jeffrey D. Dufour, Jason Mefford, Megan Pandrea, Ivona Wolinsky, Steven M. Doms, Robert W. DeMartino, Julie A. Siciliano, Salvatore J. Lyons, Kathy Springer, Martin S. Moore, John P. J Exp Med Article Human immunodeficiency virus type 1 (HIV-1) fuses with cells after sequential interactions between its envelope glycoproteins, CD4 and a coreceptor, usually CC chemokine receptor 5 (CCR5) or CXC receptor 4 (CXCR4). CMPD 167 is a CCR5-specific small molecule with potent antiviral activity in vitro. We show that CMPD 167 caused a rapid and substantial (4–200-fold) decrease in plasma viremia in six rhesus macaques chronically infected with simian immunodeficiency virus (SIV) strains SIVmac251 or SIVB670, but not in an animal infected with the X4 simian–human immunodeficiency virus (SHIV), SHIV-89.6P. In three of the SIV-infected animals, viremia reduction was sustained. In one, there was a rapid, but partial, rebound and in another, there was a rapid and complete rebound. There was a substantial delay (>21 d) between the end of therapy and the onset of full viremia rebound in two animals. We also evaluated whether vaginal administration of gel-formulated CMPD 167 could prevent vaginal transmission of the R5 virus, SHIV-162P4. Complete protection occurred in only 2 of 11 animals, but early viral replication was significantly less in the 11 CMPD 167-recipients than in 9 controls receiving carrier gel. These findings support the development of small molecule CCR5 inhibitors as antiviral therapies, and possibly as components of a topical microbicide to prevent HIV-1 sexual transmission. The Rockefeller University Press 2003-11-17 /pmc/articles/PMC2194125/ /pubmed/14623909 http://dx.doi.org/10.1084/jem.20031266 Text en Copyright © 2003, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Article Veazey, Ronald S. Klasse, Per Johan Ketas, Thomas J. Reeves, Jacqueline D. Piatak, Michael Kunstman, Kevin Kuhmann, Shawn E. Marx, Preston A. Lifson, Jeffrey D. Dufour, Jason Mefford, Megan Pandrea, Ivona Wolinsky, Steven M. Doms, Robert W. DeMartino, Julie A. Siciliano, Salvatore J. Lyons, Kathy Springer, Martin S. Moore, John P. Use of a Small Molecule CCR5 Inhibitor in Macaques to Treat Simian Immunodeficiency Virus Infection or Prevent Simian–Human Immunodeficiency Virus Infection |
title | Use of a Small Molecule CCR5 Inhibitor in Macaques to Treat Simian Immunodeficiency Virus Infection or Prevent Simian–Human Immunodeficiency Virus Infection |
title_full | Use of a Small Molecule CCR5 Inhibitor in Macaques to Treat Simian Immunodeficiency Virus Infection or Prevent Simian–Human Immunodeficiency Virus Infection |
title_fullStr | Use of a Small Molecule CCR5 Inhibitor in Macaques to Treat Simian Immunodeficiency Virus Infection or Prevent Simian–Human Immunodeficiency Virus Infection |
title_full_unstemmed | Use of a Small Molecule CCR5 Inhibitor in Macaques to Treat Simian Immunodeficiency Virus Infection or Prevent Simian–Human Immunodeficiency Virus Infection |
title_short | Use of a Small Molecule CCR5 Inhibitor in Macaques to Treat Simian Immunodeficiency Virus Infection or Prevent Simian–Human Immunodeficiency Virus Infection |
title_sort | use of a small molecule ccr5 inhibitor in macaques to treat simian immunodeficiency virus infection or prevent simian–human immunodeficiency virus infection |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2194125/ https://www.ncbi.nlm.nih.gov/pubmed/14623909 http://dx.doi.org/10.1084/jem.20031266 |
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