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      A Small-molecule Inhibitor Directed against the Chemokine Receptor CXCR4 Prevents its Use as an HIV-1 Coreceptor

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          Abstract

          The chemokine receptor CXCR4 is the major coreceptor used for cellular entry by T cell– tropic human immunodeficiency virus (HIV)-1 strains, whereas CCR5 is used by macrophage (M)-tropic strains. Here we show that a small-molecule inhibitor, ALX40-4C, inhibits HIV-1 envelope (Env)-mediated membrane fusion and viral entry directly at the level of coreceptor use. ALX40-4C inhibited HIV-1 use of the coreceptor CXCR4 by T- and dual-tropic HIV-1 strains, whereas use of CCR5 by M- and dual-tropic strains was not inhibited. Dual-tropic viruses capable of using both CXCR4 and CCR5 were inhibited by ALX40-4C only when cells expressed CXCR4 alone. ALX40-4C blocked stromal-derived factor (SDF)-1α–mediated activation of CXCR4 and binding of the monoclonal antibody 12G5 to cells expressing CXCR4. Overlap of the ALX40-4C binding site with that of 12G5 and SDF implicates direct blocking of Env interactions, rather than downregulation of receptor, as the mechanism of inhibition. Thus, ALX40-4C represents a small-molecule inhibitor of HIV-1 infection that acts directly against a chemokine receptor at the level of Env-mediated membrane fusion.

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          Most cited references26

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          Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection.

          Treatment of infected patients with ABT-538, an inhibitor of the protease of human immunodeficiency virus type 1 (HIV-1), causes plasma HIV-1 levels to decrease exponentially (mean half-life, 2.1 +/- 0.4 days) and CD4 lymphocyte counts to rise substantially. Minimum estimates of HIV-1 production and clearance and of CD4 lymphocyte turnover indicate that replication of HIV-1 in vivo is continuous and highly productive, driving the rapid turnover of CD4 lymphocytes.
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            Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells.

            Evidence suggests that CD8+ T lymphocytes are involved in the control of human immunodeficiency virus (HIV) infection in vivo, either by cytolytic mechanisms or by the release of HIV-suppressive factors (HIV-SF). The chemokines RANTES, MIP-1 alpha, and MIP-1 beta were identified as the major HIV-SF produced by CD8+ T cells. Two active proteins purified from the culture supernatant of an immortalized CD8+ T cell clone revealed sequence identity with human RANTES and MIP-1 alpha. RANTES, MIP-1 alpha, and MIP-1 beta were released by both immortalized and primary CD8+ T cells. HIV-SF activity produced by these cells was completely blocked by a combination of neutralizing antibodies against RANTES, MIP-1 alpha, and MIP-1 beta. Recombinant human RANTES, MIP-1 alpha, and MIP-1 beta induced a dose-dependent inhibition of different strains of HIV-1, HIV-2, and simian immunodeficiency virus (SIV). These data may have relevance for the prevention and therapy of AIDS.
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              HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor.

              A cofactor for HIV-1 (human immunodeficiency virus-type 1) fusion and entry was identified with the use of a novel functional complementary DNA (cDNA) cloning strategy. This protein, designated "fusin," is a putative G protein-coupled receptor with seven transmembrane segments. Recombinant fusin enabled CD4-expressing nonhuman cell types to support HIV-1 Env-mediated cell fusion and HIV-1 infection. Antibodies to fusin blocked cell fusion and infection with normal CD4-positive human target cells. Fusin messenger RNA levels correlated with HIV-1 permissiveness in diverse human cell types. Fusin acted preferentially for T cell line-tropic isolates, in comparison to its activity with macrophagetropic HIV-1 isolates.
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                Author and article information

                Journal
                J Exp Med
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                20 October 1997
                : 186
                : 8
                : 1395-1400
                Affiliations
                From the [* ]Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104; []Department of Medicine, West Los Angeles Veterans Affairs Medical Center, [§ ]University of California at Los Angeles School of Medicine, and []Cedars-Sinai Medical Center, Los Angeles, California; and []Department of Medicine, University of Texas Medical Branch, Galveston, Texas
                Author notes

                Address correspondence to William A. O'Brien, Infectious Diseases, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-0835. Phone: 409-747-2361; FAX: 409-747-0507; E-mail: wobrien@ 123456impol.utmb.edu ; or address correspondence to Robert W. Doms, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104. Phone: 1-215-898-0890; FAX: 1-215-573-2883; E-mail: doms@ 123456mail.med.upenn.edu

                Article
                2199097
                9334380
                cc8f69ae-7a57-47fb-8a76-ba38dadf6db2
                Copyright @ 1997
                History
                : 3 July 1997
                : 5 August 1997
                Categories
                Brief Definitive Report
                Brief Definitive Reports

                Medicine
                Medicine

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