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      New approaches in the treatment of HIV/AIDS – focus on maraviroc and other CCR5 antagonists

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          Abstract

          Treatment of HIV-1 infection has produced dramatic success for many patients. Nevertheless, viral resistance continues to limit the efficacy of currently available agents in many patients. The CCR5 antagonists are a new class of antiretroviral agents that target a necessary coreceptor for viral entry of many strains of HIV-1. Recently, the first agent within this class, maraviroc, was approved by a number of regulatory agencies, including the Food and Drug Administration. Herein we review the role of the CCR5 receptor in HIV-1 infection and potential methods to target it in anti-HIV-1 therapy. We review the various categories of agents and discuss specific agents that have progressed to clinical study. We discuss in detail the recently approved, first in class CCR5 antagonist, maraviroc, and discuss aspects of resistance to CCR5 antagonism and the potential role of CCR5 antagonism in the management of HIV-1 infection.

          Most cited references127

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          Core structure of gp41 from the HIV envelope glycoprotein.

          The envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1) consists of a complex of gp120 and gp41. gp120 determines viral tropism by binding to target-cell receptors, while gp41 mediates fusion between viral and cellular membranes. Previous studies identified an alpha-helical domain within gp41 composed of a trimer of two interacting peptides. The crystal structure of this complex, composed of the peptides N36 and C34, is a six-helical bundle. Three N36 helices form an interior, parallel coiled-coil trimer, while three C34 helices pack in an oblique, antiparallel manner into highly conserved, hydrophobic grooves on the surface of this trimer. This structure shows striking similarity to the low-pH-induced conformation of influenza hemagglutinin and likely represents the core of fusion-active gp41. Avenues for the design/discovery of small-molecule inhibitors of HIV infection are directly suggested by this structure.
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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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              Mechanisms of viral membrane fusion and its inhibition.

              Viral envelope glycoproteins promote viral infection by mediating the fusion of the viral membrane with the host-cell membrane. Structural and biochemical studies of two viral glycoproteins, influenza hemagglutinin and HIV-1 envelope protein, have led to a common model for viral entry. The fusion mechanism involves a transient conformational species that can be targeted by therapeutic strategies. This mechanism of infectivity is likely utilized by a wide variety of enveloped viruses for which similar therapeutic interventions should be possible.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                April 2008
                April 2008
                : 4
                : 2
                : 473-485
                Affiliations
                [1 ]Department of Medicine (Infectious Diseases), Hahnemann University Hospital, Drexel University College of Medicine Philadelphia, PA, USA
                [2 ]Department of Medicine, (Hematology/Oncology), Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA
                [3 ]Department of Medicine (Hematology/Oncology), Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA
                Author notes
                Correspondence: Hans P Schlecht Drexel University College of Medicine, Mail Stop 461, 245 N. 15th Street, Philadelphia, PA, 19102-1192, USA Tel +1 215 762 6794 Fax +1 215 762 3031 Email hans.schlecht@ 123456drexelmed.edu
                Article
                2504054
                18728830
                ac720968-adac-4efb-9d6d-84c7981b526b
                © 2008 Dove Medical Press Limited. All rights reserved
                History
                Categories
                Review

                Medicine
                coreceptor,viral entry,maraviroc,ccr5,chemokine receptor,hiv-1 tropism
                Medicine
                coreceptor, viral entry, maraviroc, ccr5, chemokine receptor, hiv-1 tropism

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