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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

  1. Author:
    Veazey, R. S.
    Klasse, P. J.
    Ketas, T. J.
    Reeves, J. D.
    Piatak, M.
    Kunstman, K.
    Kuhmann, S. E.
    Marx, P. A.
    Lifson, J. D.
    Dufour, J.
    Mefford, M.
    Pandrea, I.
    Wolinsky, S. M.
    Doms, R. W.
    DeMartino, J. A.
    Siciliano, S. J.
    Lyons, K.
    Springer, M. S.
    Moore, J. P.

  2. Author Address

    Cornell Univ, Weill Med Coll, Dept Microbiol & Immunol, 1300 York Ave,W-805, New York, NY 10021 USA Cornell Univ, Weill Med Coll, Dept Microbiol & Immunol, New York, NY 10021 USA Tulane Univ, Hlth Sci Ctr, Tulane Natl Primate Res Ctr, Covington, LA 70433 USA Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA NCI, Sci Applicat Int Corp Frederick Inc, AIDS Vaccine Program, Retroviral Pathogenesis Lab, Frederick, MD 20702 USA Northwestern Univ, Feinberg Sch Med, Div Infect Dis, Chicago, IL 60611 USA Merck Res Labs, Dept Immunol & Rheumatol, Rahway, NJ 07065 USA Merck Res Labs, Dept Med Chem, Rahway, NJ 07065 USA Merck Res Labs, Dept Atherosclerosis & Endocrinol, Rahway, NJ 07065 USA Moore JP Cornell Univ, Weill Med Coll, Dept Microbiol & Immunol, 1300 York Ave,W-805, New York, NY 10021 USA
    1. Year: 2003
  2. Journal: Journal of Experimental Medicine
    1. 198
    2. 10
    3. Pages: 1551-1562
  4. Type of Article: Article
  1. Abstract:

    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 CCK5-specific small molecule with potent antiviral activity in vitro. We show that CMPD 167 caused a rapid and substantial (4200-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.

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