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Israel F Charo - One of the best experts on this subject based on the ideXlab platform.

  • selective employment of Chemokine Receptors as human immunodeficiency virus type 1 coReceptors determined by individual amino acids within the envelope v3 loop
    Journal of Virology, 1997
    Co-Authors: Roberto F Speck, Kathy Wehrly, Emily J Platt, Robert E Atchison, Israel F Charo, David Kabat, Bruce Chesebro, Mark A Goldsmith
    Abstract:

    The Chemokine Receptor CCR5 acts as an essential cofactor for cell entry by macrophage-tropic human immunodeficiency virus type 1 (HIV-1) strains, whereas CXCR4 acts as an essential cofactor for T-cell-line-adapted strains. We demonstrated that the specific amino acids in the V3 loop of the HIV-1 envelope protein that determine cellular tropism also regulate Chemokine coReceptor preference for cell entry by the virus. Further, a strong correlation was found between HIV-1 strains classified as syncytium inducing in standard assays and those using CXCR4 as a coReceptor. These data support the hypothesis that progressive adaptation to additional coReceptors is a key molecular basis for HIV-1 phenotypic evolution in vivo.

  • multiple extracellular elements of CCR5 and hiv 1 entry dissociation from response to Chemokines
    Science, 1996
    Co-Authors: Robert E Atchison, Israel F Charo, Jennifa Gosling, Felipe S Monteclaro, Christian Franci, Laura Digilio, Mark A Goldsmith
    Abstract:

    The human beta-Chemokine Receptor CCR5 is an important cofactor for entry of human immunodeficiency virus-type 1 (HIV-1). The murine form of CCR5, despite its 82 percent identity to the human form, was not functional as an HIV-1 coReceptor. HIV-1 entry function could be reconstituted by fusion of various individual elements derived from the extracellular region of human CCR5 onto murine CCR5. Analysis of chimeras containing elements from human CCR5 and human CCR2B suggested that a complex structure rather than single contact sites is responsible for facilitation of viral entry. Further, certain chimeras lacking the domains necessary to signal in response to their natural Chemokine ligands retained vigorous HIV-1 coReceptor activity.

  • multiple extracellular elements of CCR5 and hiv 1 entry dissociation from response to Chemokines
    Science, 1996
    Co-Authors: Robert E Atchison, Israel F Charo, Jennifa Gosling, Felipe S Monteclaro, Christian Franci, Laura Digilio, Mark A Goldsmith
    Abstract:

    The human β-Chemokine Receptor CCR5 is an important cofactor for entry of human immunodeficiency virus-type 1 (HIV-1). The murine form of CCR5, despite its 82 percent identity to the human form, was not functional as an HIV-1 coReceptor. HIV-1 entry function could be reconstituted by fusion of various individual elements derived from the extracellular region of human CCR5 onto murine CCR5. Analysis of chimeras containing elements from human CCR5 and human CCR2B suggested that a complex structure rather than single contact sites is responsible for facilitation of viral entry. Further, certain chimeras lacking the domains necessary to signal in response to their natural Chemokine ligands retained vigorous HIV-1 coReceptor activity.

  • molecular cloning and functional characterization of a novel human cc Chemokine Receptor CCR5 for rantes mip 1beta and mip 1alpha
    Journal of Biological Chemistry, 1996
    Co-Authors: Carol J Raport, Jennifa Gosling, Vicki L Schweickart, Patrick W Gray, Israel F Charo
    Abstract:

    Abstract Chemokines affect leukocyte chemotactic and activation activities through specific G protein-coupled Receptors. In an effort to map the closely linked CC Chemokine Receptor genes, we identified a novel Chemokine Receptor encoded 18 kilobase pairs downstream of the monocyte chemoattractant protein-1 (MCP-1) Receptor (CCR2) gene on human chromosome 3p21. The deduced amino acid sequence of this novel Receptor, designated CCR5, is most similar to CCR2B, sharing 71% identical residues. Transfected cells expressing the Receptor bind RANTES (regulated on activation normal T cell expressed), MIP-1β, and MIP-1α with high affinity and generate inositol phosphates in response to these Chemokines. This same combination of Chemokines has recently been shown to potently inhibit human immunodeficiency virus replication in human peripheral blood leukocytes (Cocchi, F., DeVico, A. L., Garzino-Demo, A., Arya, S. K., Gallo, R. C., and Lusso, P. (1995) Science 270, 1811-1815). CCR5 is expressed in lymphoid organs such as thymus and spleen, as well as in peripheral blood leukocytes, including macrophages and T cells, and is the first example of a human Chemokine Receptor that signals in response to MIP-1β.

  • molecular cloning and functional characterization of a novel human cc Chemokine Receptor CCR5 for rantes mip 1β and mip 1α
    Journal of Biological Chemistry, 1996
    Co-Authors: Carol J Raport, Jennifa Gosling, Vicki L Schweickart, Patrick W Gray, Israel F Charo
    Abstract:

    Abstract Chemokines affect leukocyte chemotactic and activation activities through specific G protein-coupled Receptors. In an effort to map the closely linked CC Chemokine Receptor genes, we identified a novel Chemokine Receptor encoded 18 kilobase pairs downstream of the monocyte chemoattractant protein-1 (MCP-1) Receptor (CCR2) gene on human chromosome 3p21. The deduced amino acid sequence of this novel Receptor, designated CCR5, is most similar to CCR2B, sharing 71% identical residues. Transfected cells expressing the Receptor bind RANTES (regulated on activation normal T cell expressed), MIP-1β, and MIP-1α with high affinity and generate inositol phosphates in response to these Chemokines. This same combination of Chemokines has recently been shown to potently inhibit human immunodeficiency virus replication in human peripheral blood leukocytes (Cocchi, F., DeVico, A. L., Garzino-Demo, A., Arya, S. K., Gallo, R. C., and Lusso, P. (1995) Science 270, 1811-1815). CCR5 is expressed in lymphoid organs such as thymus and spleen, as well as in peripheral blood leukocytes, including macrophages and T cells, and is the first example of a human Chemokine Receptor that signals in response to MIP-1β.

Michael Farzan - One of the best experts on this subject based on the ideXlab platform.

  • sialylated o glycans and sulfated tyrosines in the nh2 terminal domain of cc Chemokine Receptor 5 contribute to high affinity binding of Chemokines
    Journal of Experimental Medicine, 2001
    Co-Authors: Norbert Bannert, Michael Farzan, Hyeryun Choe, Stewart Craig, Dodzie Sogah, Niki Villanueva Santo, Joseph Sodroski
    Abstract:

    The Chemokine Receptor CCR5 plays an important role in leukocyte chemotaxis and activation, and also acts as a coReceptor for human and simian immunodeficiency viruses (HIV-1, HIV-2, and SIV). We provide evidence that CCR5 is O-glycosylated on serine 6 in the NH2 terminus. The O-linked glycans, particularly sialic acid moieties, significantly contribute to binding of the Chemokine ligands. By contrast, removal of O-linked oligosaccharide exerted little effect on HIV-1 infection. Sulfation of specific tyrosine residues in the CCR5 NH2 terminus was important for efficient β-Chemokine binding. Thus, as has been observed for the binding of selectins and their ligands, O-linked carbohydrates and tyrosine sulfates play major roles in promoting the interaction of Chemokines with CCR5. The resulting flexible arrays of negative charges on the CCR5 surface may allow specific, high-affinity interactions with diverse Chemokine ligands. Although this is the first example of O-linked oligosaccharides and tyrosine sulfates playing a role in Chemokine binding, the high density of serines, threonines and tyrosines in the N-termini of many CC Chemokine Receptors suggests that these posttranslational modifications may commonly contribute to Chemokine binding.

  • tyrosine sulfation of the amino terminus of CCR5 facilitates hiv 1 entry
    Cell, 1999
    Co-Authors: Michael Farzan, Tajib Mirzabekov, Peter Kolchinsky, Richard T Wyatt, Mark Cayabyab, Norma P Gerard, Craig Gerard, Joseph Sodroski
    Abstract:

    Chemokine Receptors and related seven-transmembrane-segment (7TMS) Receptors serve as coReceptors for entry of human and simian immunodeficiency viruses (HIV-1, HIV-2, and SIV) into target cells. Each of these otherwise diverse coReceptors contains an N-terminal region that is acidic and tyrosine rich. Here, we show that the Chemokine Receptor CCR5, a principal HIV-1 coReceptor, is posttranslationally modified by O-linked glycosylation and by sulfation of its N-terminal tyrosines. Sulfated tyrosines contribute to the binding of CCR5 to MIP-1 alpha, MIP-1 beta, and HIV-1 gp120/CD4 complexes and to the ability of HIV-1 to enter cells expressing CCR5 and CD4. CXCR4, another important HIV-1 coReceptor, is also sulfated. Tyrosine sulfation may contribute to the natural function of many 7TMS Receptors and may be a modification common to primate immunodeficiency virus coReceptors.

  • the orphan seven transmembrane Receptor apj supports the entry of primary t cell line tropic and dualtropic human immunodeficiency virus type 1
    Journal of Virology, 1998
    Co-Authors: Hyeryun Choe, Luisa Marcon, Michael Farzan, Kathleen A. Martin, Mark Cayabyab, Miriam K Konkel, Michael Berman, M E Dorf
    Abstract:

    Human immunodeficiency virus type 1 (HIV-1) enters target cells by sequential binding to CD4 and specific seven-transmembrane-segment (7TMS) coReceptors. Viruses use the Chemokine Receptor CCR5 as a coReceptor in the early, asymptomatic stages of HIV-1 infection but can adapt to the use of other Receptors such as CXCR4 and CCR3 as the infection proceeds. Here we identify one such coReceptor, Apj, which supported the efficient entry of several primary T-cell-line tropic (T-tropic) and dualtropic HIV-1 isolates and the simian immunodeficiency virus SIVmac316. Another 7TMS protein, CCR9, supported the less efficient entry of one primary T-tropic isolate. mRNAs for both Receptors were present in phytohemagglutinin- and interleukin-2-activated peripheral blood mononuclear cells. Apj and CCR9 share with other coReceptors for HIV-1 and SIV an N-terminal region rich in aromatic and acidic residues. These results highlight properties common to 7TMS proteins that can function as HIV-1 coReceptors, and they may contribute to an understanding of viral evolution in infected individuals.

  • two orphan seven transmembrane segment Receptors which are expressed in cd4 positive cells support simian immunodeficiency virus infection
    Journal of Experimental Medicine, 1997
    Co-Authors: Michael Farzan, Gunilla B Karlsson, Peter L Barrett, Nathalie Marchand, Luisa Marcon, Hyeryun Choe, Kathleen A. Martin, Wolfgang Hofmann, Nancy Sullivan
    Abstract:

    Clinical isolates of primate immunodeficiency viruses, including human immunodeficiency virus type 1 (HIV-1), enter target cells by sequential binding to CD4 and the Chemokine Receptor CCR5, a member of the seven-transmembrane Receptor family. HIV-1 variants which use additional Chemokine Receptors are present in the central nervous system or emerge during the course of infection. Simian immunodeficiency viruses (SIV) have been shown to use CCR5 as a coReceptor, but no other Receptors for these viruses have been identified. Here we show that two orphan seven-transmembrane segment Receptors, gpr1 and gpr15, serve as coReceptors for SIV, and are expressed in human alveolar macrophages. The more efficient of these, gpr15, is also expressed in human CD4+ T lymphocytes and activated rhesus macaque peripheral blood mononuclear cells. The gpr15 and gpr1 proteins lack several hallmarks of Chemokine Receptors, but share with CCR5 an amino-terminal motif rich in tyrosine residues. These results underscore the potential diversity of seven-transmembrane segment Receptors used as entry cofactors by primate immunodeficiency viruses, and may contribute to an understanding of viral variation and pathogenesis.

  • hiv 1 entry and macrophage inflammatory protein 1β mediated signaling are independent functions of the Chemokine Receptor CCR5
    Journal of Biological Chemistry, 1997
    Co-Authors: Michael Farzan, Hyeryun Choe, Mary Sidelko, Charles R Mackay, Kathleen A. Martin, Joseph Sodroski
    Abstract:

    Abstract The human immunodeficiency virus type 1 (HIV-1) requires the presence of specific Chemokine Receptors in addition to CD4 to enter its target cell. The Chemokine Receptor CCR5 is used by macrophage-tropic strains of HIV-1, which predominate during the asymptomatic stages of infection. Here we investigate whether the ability of CCR5 to signal in response to its β-Chemokine ligands is necessary or sufficient for viral entry. Three CCR5 mutants with little or no ability to mobilize calcium in response to macrophage inflammatory protein-1β could nonetheless support HIV-1 entry and the early steps in the virus life cycle with efficiencies comparable with those of wild-type CCR5. Conversely, a chimeric Receptor with the N terminus of CCR2 replacing that of CCR5 responded to macrophage inflammatory protein-1β and MCP-1 but did not efficiently support viral entry. These results demonstrate that Chemokine signaling and HIV-1 entry are separable functions of CCR5 and that only viral entry requires the N-terminal domain of CCR5.

Joseph Sodroski - One of the best experts on this subject based on the ideXlab platform.

  • sialylated o glycans and sulfated tyrosines in the nh2 terminal domain of cc Chemokine Receptor 5 contribute to high affinity binding of Chemokines
    Journal of Experimental Medicine, 2001
    Co-Authors: Norbert Bannert, Michael Farzan, Hyeryun Choe, Stewart Craig, Dodzie Sogah, Niki Villanueva Santo, Joseph Sodroski
    Abstract:

    The Chemokine Receptor CCR5 plays an important role in leukocyte chemotaxis and activation, and also acts as a coReceptor for human and simian immunodeficiency viruses (HIV-1, HIV-2, and SIV). We provide evidence that CCR5 is O-glycosylated on serine 6 in the NH2 terminus. The O-linked glycans, particularly sialic acid moieties, significantly contribute to binding of the Chemokine ligands. By contrast, removal of O-linked oligosaccharide exerted little effect on HIV-1 infection. Sulfation of specific tyrosine residues in the CCR5 NH2 terminus was important for efficient β-Chemokine binding. Thus, as has been observed for the binding of selectins and their ligands, O-linked carbohydrates and tyrosine sulfates play major roles in promoting the interaction of Chemokines with CCR5. The resulting flexible arrays of negative charges on the CCR5 surface may allow specific, high-affinity interactions with diverse Chemokine ligands. Although this is the first example of O-linked oligosaccharides and tyrosine sulfates playing a role in Chemokine binding, the high density of serines, threonines and tyrosines in the N-termini of many CC Chemokine Receptors suggests that these posttranslational modifications may commonly contribute to Chemokine binding.

  • tyrosine sulfation of the amino terminus of CCR5 facilitates hiv 1 entry
    Cell, 1999
    Co-Authors: Michael Farzan, Tajib Mirzabekov, Peter Kolchinsky, Richard T Wyatt, Mark Cayabyab, Norma P Gerard, Craig Gerard, Joseph Sodroski
    Abstract:

    Chemokine Receptors and related seven-transmembrane-segment (7TMS) Receptors serve as coReceptors for entry of human and simian immunodeficiency viruses (HIV-1, HIV-2, and SIV) into target cells. Each of these otherwise diverse coReceptors contains an N-terminal region that is acidic and tyrosine rich. Here, we show that the Chemokine Receptor CCR5, a principal HIV-1 coReceptor, is posttranslationally modified by O-linked glycosylation and by sulfation of its N-terminal tyrosines. Sulfated tyrosines contribute to the binding of CCR5 to MIP-1 alpha, MIP-1 beta, and HIV-1 gp120/CD4 complexes and to the ability of HIV-1 to enter cells expressing CCR5 and CD4. CXCR4, another important HIV-1 coReceptor, is also sulfated. Tyrosine sulfation may contribute to the natural function of many 7TMS Receptors and may be a modification common to primate immunodeficiency virus coReceptors.

  • hiv 1 entry and macrophage inflammatory protein 1β mediated signaling are independent functions of the Chemokine Receptor CCR5
    Journal of Biological Chemistry, 1997
    Co-Authors: Michael Farzan, Hyeryun Choe, Mary Sidelko, Charles R Mackay, Kathleen A. Martin, Joseph Sodroski
    Abstract:

    Abstract The human immunodeficiency virus type 1 (HIV-1) requires the presence of specific Chemokine Receptors in addition to CD4 to enter its target cell. The Chemokine Receptor CCR5 is used by macrophage-tropic strains of HIV-1, which predominate during the asymptomatic stages of infection. Here we investigate whether the ability of CCR5 to signal in response to its β-Chemokine ligands is necessary or sufficient for viral entry. Three CCR5 mutants with little or no ability to mobilize calcium in response to macrophage inflammatory protein-1β could nonetheless support HIV-1 entry and the early steps in the virus life cycle with efficiencies comparable with those of wild-type CCR5. Conversely, a chimeric Receptor with the N terminus of CCR2 replacing that of CCR5 responded to macrophage inflammatory protein-1β and MCP-1 but did not efficiently support viral entry. These results demonstrate that Chemokine signaling and HIV-1 entry are separable functions of CCR5 and that only viral entry requires the N-terminal domain of CCR5.

Hyeryun Choe - One of the best experts on this subject based on the ideXlab platform.

  • sialylated o glycans and sulfated tyrosines in the nh2 terminal domain of cc Chemokine Receptor 5 contribute to high affinity binding of Chemokines
    Journal of Experimental Medicine, 2001
    Co-Authors: Norbert Bannert, Michael Farzan, Hyeryun Choe, Stewart Craig, Dodzie Sogah, Niki Villanueva Santo, Joseph Sodroski
    Abstract:

    The Chemokine Receptor CCR5 plays an important role in leukocyte chemotaxis and activation, and also acts as a coReceptor for human and simian immunodeficiency viruses (HIV-1, HIV-2, and SIV). We provide evidence that CCR5 is O-glycosylated on serine 6 in the NH2 terminus. The O-linked glycans, particularly sialic acid moieties, significantly contribute to binding of the Chemokine ligands. By contrast, removal of O-linked oligosaccharide exerted little effect on HIV-1 infection. Sulfation of specific tyrosine residues in the CCR5 NH2 terminus was important for efficient β-Chemokine binding. Thus, as has been observed for the binding of selectins and their ligands, O-linked carbohydrates and tyrosine sulfates play major roles in promoting the interaction of Chemokines with CCR5. The resulting flexible arrays of negative charges on the CCR5 surface may allow specific, high-affinity interactions with diverse Chemokine ligands. Although this is the first example of O-linked oligosaccharides and tyrosine sulfates playing a role in Chemokine binding, the high density of serines, threonines and tyrosines in the N-termini of many CC Chemokine Receptors suggests that these posttranslational modifications may commonly contribute to Chemokine binding.

  • the orphan seven transmembrane Receptor apj supports the entry of primary t cell line tropic and dualtropic human immunodeficiency virus type 1
    Journal of Virology, 1998
    Co-Authors: Hyeryun Choe, Luisa Marcon, Michael Farzan, Kathleen A. Martin, Mark Cayabyab, Miriam K Konkel, Michael Berman, M E Dorf
    Abstract:

    Human immunodeficiency virus type 1 (HIV-1) enters target cells by sequential binding to CD4 and specific seven-transmembrane-segment (7TMS) coReceptors. Viruses use the Chemokine Receptor CCR5 as a coReceptor in the early, asymptomatic stages of HIV-1 infection but can adapt to the use of other Receptors such as CXCR4 and CCR3 as the infection proceeds. Here we identify one such coReceptor, Apj, which supported the efficient entry of several primary T-cell-line tropic (T-tropic) and dualtropic HIV-1 isolates and the simian immunodeficiency virus SIVmac316. Another 7TMS protein, CCR9, supported the less efficient entry of one primary T-tropic isolate. mRNAs for both Receptors were present in phytohemagglutinin- and interleukin-2-activated peripheral blood mononuclear cells. Apj and CCR9 share with other coReceptors for HIV-1 and SIV an N-terminal region rich in aromatic and acidic residues. These results highlight properties common to 7TMS proteins that can function as HIV-1 coReceptors, and they may contribute to an understanding of viral evolution in infected individuals.

  • two orphan seven transmembrane segment Receptors which are expressed in cd4 positive cells support simian immunodeficiency virus infection
    Journal of Experimental Medicine, 1997
    Co-Authors: Michael Farzan, Gunilla B Karlsson, Peter L Barrett, Nathalie Marchand, Luisa Marcon, Hyeryun Choe, Kathleen A. Martin, Wolfgang Hofmann, Nancy Sullivan
    Abstract:

    Clinical isolates of primate immunodeficiency viruses, including human immunodeficiency virus type 1 (HIV-1), enter target cells by sequential binding to CD4 and the Chemokine Receptor CCR5, a member of the seven-transmembrane Receptor family. HIV-1 variants which use additional Chemokine Receptors are present in the central nervous system or emerge during the course of infection. Simian immunodeficiency viruses (SIV) have been shown to use CCR5 as a coReceptor, but no other Receptors for these viruses have been identified. Here we show that two orphan seven-transmembrane segment Receptors, gpr1 and gpr15, serve as coReceptors for SIV, and are expressed in human alveolar macrophages. The more efficient of these, gpr15, is also expressed in human CD4+ T lymphocytes and activated rhesus macaque peripheral blood mononuclear cells. The gpr15 and gpr1 proteins lack several hallmarks of Chemokine Receptors, but share with CCR5 an amino-terminal motif rich in tyrosine residues. These results underscore the potential diversity of seven-transmembrane segment Receptors used as entry cofactors by primate immunodeficiency viruses, and may contribute to an understanding of viral variation and pathogenesis.

  • hiv 1 entry and macrophage inflammatory protein 1β mediated signaling are independent functions of the Chemokine Receptor CCR5
    Journal of Biological Chemistry, 1997
    Co-Authors: Michael Farzan, Hyeryun Choe, Mary Sidelko, Charles R Mackay, Kathleen A. Martin, Joseph Sodroski
    Abstract:

    Abstract The human immunodeficiency virus type 1 (HIV-1) requires the presence of specific Chemokine Receptors in addition to CD4 to enter its target cell. The Chemokine Receptor CCR5 is used by macrophage-tropic strains of HIV-1, which predominate during the asymptomatic stages of infection. Here we investigate whether the ability of CCR5 to signal in response to its β-Chemokine ligands is necessary or sufficient for viral entry. Three CCR5 mutants with little or no ability to mobilize calcium in response to macrophage inflammatory protein-1β could nonetheless support HIV-1 entry and the early steps in the virus life cycle with efficiencies comparable with those of wild-type CCR5. Conversely, a chimeric Receptor with the N terminus of CCR2 replacing that of CCR5 responded to macrophage inflammatory protein-1β and MCP-1 but did not efficiently support viral entry. These results demonstrate that Chemokine signaling and HIV-1 entry are separable functions of CCR5 and that only viral entry requires the N-terminal domain of CCR5.

Kathleen A. Martin - One of the best experts on this subject based on the ideXlab platform.

  • the orphan seven transmembrane Receptor apj supports the entry of primary t cell line tropic and dualtropic human immunodeficiency virus type 1
    Journal of Virology, 1998
    Co-Authors: Hyeryun Choe, Luisa Marcon, Michael Farzan, Kathleen A. Martin, Mark Cayabyab, Miriam K Konkel, Michael Berman, M E Dorf
    Abstract:

    Human immunodeficiency virus type 1 (HIV-1) enters target cells by sequential binding to CD4 and specific seven-transmembrane-segment (7TMS) coReceptors. Viruses use the Chemokine Receptor CCR5 as a coReceptor in the early, asymptomatic stages of HIV-1 infection but can adapt to the use of other Receptors such as CXCR4 and CCR3 as the infection proceeds. Here we identify one such coReceptor, Apj, which supported the efficient entry of several primary T-cell-line tropic (T-tropic) and dualtropic HIV-1 isolates and the simian immunodeficiency virus SIVmac316. Another 7TMS protein, CCR9, supported the less efficient entry of one primary T-tropic isolate. mRNAs for both Receptors were present in phytohemagglutinin- and interleukin-2-activated peripheral blood mononuclear cells. Apj and CCR9 share with other coReceptors for HIV-1 and SIV an N-terminal region rich in aromatic and acidic residues. These results highlight properties common to 7TMS proteins that can function as HIV-1 coReceptors, and they may contribute to an understanding of viral evolution in infected individuals.

  • two orphan seven transmembrane segment Receptors which are expressed in cd4 positive cells support simian immunodeficiency virus infection
    Journal of Experimental Medicine, 1997
    Co-Authors: Michael Farzan, Gunilla B Karlsson, Peter L Barrett, Nathalie Marchand, Luisa Marcon, Hyeryun Choe, Kathleen A. Martin, Wolfgang Hofmann, Nancy Sullivan
    Abstract:

    Clinical isolates of primate immunodeficiency viruses, including human immunodeficiency virus type 1 (HIV-1), enter target cells by sequential binding to CD4 and the Chemokine Receptor CCR5, a member of the seven-transmembrane Receptor family. HIV-1 variants which use additional Chemokine Receptors are present in the central nervous system or emerge during the course of infection. Simian immunodeficiency viruses (SIV) have been shown to use CCR5 as a coReceptor, but no other Receptors for these viruses have been identified. Here we show that two orphan seven-transmembrane segment Receptors, gpr1 and gpr15, serve as coReceptors for SIV, and are expressed in human alveolar macrophages. The more efficient of these, gpr15, is also expressed in human CD4+ T lymphocytes and activated rhesus macaque peripheral blood mononuclear cells. The gpr15 and gpr1 proteins lack several hallmarks of Chemokine Receptors, but share with CCR5 an amino-terminal motif rich in tyrosine residues. These results underscore the potential diversity of seven-transmembrane segment Receptors used as entry cofactors by primate immunodeficiency viruses, and may contribute to an understanding of viral variation and pathogenesis.

  • hiv 1 entry and macrophage inflammatory protein 1β mediated signaling are independent functions of the Chemokine Receptor CCR5
    Journal of Biological Chemistry, 1997
    Co-Authors: Michael Farzan, Hyeryun Choe, Mary Sidelko, Charles R Mackay, Kathleen A. Martin, Joseph Sodroski
    Abstract:

    Abstract The human immunodeficiency virus type 1 (HIV-1) requires the presence of specific Chemokine Receptors in addition to CD4 to enter its target cell. The Chemokine Receptor CCR5 is used by macrophage-tropic strains of HIV-1, which predominate during the asymptomatic stages of infection. Here we investigate whether the ability of CCR5 to signal in response to its β-Chemokine ligands is necessary or sufficient for viral entry. Three CCR5 mutants with little or no ability to mobilize calcium in response to macrophage inflammatory protein-1β could nonetheless support HIV-1 entry and the early steps in the virus life cycle with efficiencies comparable with those of wild-type CCR5. Conversely, a chimeric Receptor with the N terminus of CCR2 replacing that of CCR5 responded to macrophage inflammatory protein-1β and MCP-1 but did not efficiently support viral entry. These results demonstrate that Chemokine signaling and HIV-1 entry are separable functions of CCR5 and that only viral entry requires the N-terminal domain of CCR5.