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      C-C chemokine receptor type five (CCR5): An emerging target for the control of HIV infection

      , *

      Applied & Translational Genomics

      Elsevier

      CCR5, HIV, Δ32, Therapeutics

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          Abstract

          When HIV was initially discovered as the causative agent of AIDS, many expected to find a vaccine within a few years. This has however proven to be elusive; it has been approximately 30 years since HIV was first discovered, and a suitable vaccine is still not in effect. In 2009, a paper published by Hutter et al. reported on a bone marrow transplant performed on an HIV positive individual using stem cells that were derived from a donor who was homozygous for a mutation in the CCR5 gene known as CCR5 delta-32 (Δ32) ( Hütter et al., 2009). The HIV positive individual became HIV negative and remained free of viral detection after transplantation despite having halted anti-retroviral (ARV) treatment. This review will focus on CCR5 as a key component in HIV immunity and will discuss the role of CCR5 in the control of HIV infection.

          Highlights

          • Overview of the CCR5 receptor, gene and protein structure

          • The role of CCR5 in HIV infection and progression

          • CCR5 gene mutations affecting HIV including detail on South African mutations

          • Details of the CCR5 Δ32 mutation

          • Current therapeutic applications of CCR5 for HIV

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          Most cited references 172

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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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            Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study.

            The chemokine receptor 5 (CKR5) protein serves as a secondary receptor on CD4(+) T lymphocytes for certain strains of human immunodeficiency virus-type 1 (HIV-1). The CKR5 structural gene was mapped to human chromosome 3p21, and a 32-base pair deletion allele (CKR5Delta32) was identified that is present at a frequency of approximately0.10 in the Caucasian population of the United States. An examination of 1955 patients included among six well-characterized acquired immunodeficiency syndrome (AIDS) cohort studies revealed that 17 deletion homozygotes occurred exclusively among 612 exposed HIV-1 antibody-negative individuals (2.8 percent) and not at all in 1343 HIV-1-infected individuals. The frequency of CKR5 deletion heterozygotes was significantly elevated in groups of individuals that had survived HIV-1 infection for more than 10 years, and, in some risk groups, twice as frequent as their occurrence in rapid progressors to AIDS. Survival analysis clearly shows that disease progression is slower in CKR5 deletion heterozygotes than in individuals homozygous for the normal CKR5 gene. The CKR5Delta32 deletion may act as a recessive restriction gene against HIV-1 infection and may exert a dominant phenotype of delaying progression to AIDS among infected individuals.
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              The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates.

              We examined the ability of chemokine receptors and related G protein-coupled receptors to facilitate infection by primary, clinical HIV-1 isolates. CCR5, when expressed along with CD4, the HIV-1 receptor, allowed cell lines resistant to most primary HIV-1 isolates to be infected. CCR3 facilitated infection by a more restricted subset of primary viruses, and binding of the CCR3 ligand, eotaxin, inhibited infection by these isolates. Utilization of CCR3 and CCR5 on the target cell depended upon the sequence of the third variable (V3) region of the HIV-1 gp120 exterior envelope glycoprotein. The ability of various members of the chemokine receptor family to support the early stages of HIV-1 infection helps to explain viral tropism and beta-chemokine inhibition of primary HIV-1 isolates.
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                Author and article information

                Contributors
                Journal
                Appl Transl Genom
                Appl Transl Genom
                Applied & Translational Genomics
                Elsevier
                2212-0661
                26 May 2013
                01 December 2013
                26 May 2013
                : 2
                : 3-16
                Affiliations
                Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
                Institute for Cellular and Molecular Medicine, University of Pretoria, Pretoria, South Africa
                Author notes
                [* ]Corresponding author at: Dept. of Immunology, Faculty of Health Sciences, University of Pretoria, P.O. Box 2034, Pretoria 0001, South Africa. Tel.: + 27 12 319 2190; fax: + 27 12 319 2946. michael.pepper@ 123456up.ac.za
                Article
                S2212-0661(13)00008-2
                10.1016/j.atg.2013.05.004
                5133339
                27942440
                © 2013 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

                Categories
                Review

                ccr5, therapeutics, δ32, hiv

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