R5 HIV Productively Infects Langerhans Cells, and Infection Levels Are Regulated by Compound CCR5 Polymorphisms
Langerhans cells (LCs) are suspected to be initial targets for HIV after sexual exposure (by becoming infected or by capturing virus). Here, productive R5 HIV infection of LC ex vivo and LC-mediated transmission of virus to CD4+T cells were both found to depend on CCR5. By contrast, infection of mon...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 100; no. 14; pp. 8401 - 8406 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
08.07.2003
National Acad Sciences |
Subjects | |
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Abstract | Langerhans cells (LCs) are suspected to be initial targets for HIV after sexual exposure (by becoming infected or by capturing virus). Here, productive R5 HIV infection of LC ex vivo and LC-mediated transmission of virus to CD4+T cells were both found to depend on CCR5. By contrast, infection of monocyte-derived dendritic cells and transfer of infection from monocyte-derived dendritic cells to CD4+T cells were mediated by CCR5-dependent as well as DC-specific ICAM-3-grabbing nonintegrin-dependent pathways. Furthermore, in 62 healthy individuals, R5 HIV infection levels in LCs ex vivo were associated with CCR5 genotype. Specifically, genotyping for ORFΔ 32 revealed that LCs isolated from ORFΔ 32/wt individuals were significantly less susceptible to HIV when compared with LCs isolated from ORFwt/wt individuals (P = 0.016). Strikingly, further genetic analyses of the A-2459G CCR5 promoter polymorphism in ORFΔ 32/wt heterozygous individuals revealed that LCs isolated from -2459A/G + ORFΔ 32/wt individuals were markedly less susceptible to HIV than were LCs from -2459A/A + ORFΔ 32/wt individuals (P = 0.012). Interestingly, these genetic susceptibility data in LCs parallel those of genetic susceptibility studies performed in cohorts of HIV-infected individuals. Thus, we suggest that CCR5-mediated infection of LCs, and not capture of virus by LCs, provides a biologic basis for understanding certain aspects of host genetic susceptibility to initial HIV infection. |
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AbstractList | Langerhans cells (LCs) are suspected to be initial targets for HIV after sexual exposure (by becoming infected or by capturing virus). Here, productive R5 HIV infection of LC ex vivo and LC-mediated transmission of virus to CD4+ T cells were both found to depend on CCR5. By contrast, infection of monocyte-derived dendritic cells and transfer of infection from monocyte-derived dendritic cells to CD4+ T cells were mediated by CCR5-dependent as well as DC-specific ICAM-3-grabbing nonintegrin-dependent pathways. Furthermore, in 62 healthy individuals, R5 HIV infection levels in LCs ex vivo were associated with CCR5 genotype. Specifically, genotyping for ORF Delta 32 revealed that LCs isolated from ORF Delta 32/wt individuals were significantly less susceptible to HIV when compared with LCs isolated from ORFwt/wt individuals (P = 0.016). Strikingly, further genetic analyses of the A-2459G CCR5 promoter polymorphism in ORF Delta 32/wt heterozygous individuals revealed that LCs isolated from -2459A/G + ORF Delta 32/wt individuals were markedly less susceptible to HIV than were LCs from -2459A/A + ORF Delta 32/wt individuals (P = 0.012). Interestingly, these genetic susceptibility data in LCs parallel those of genetic susceptibility studies performed in cohorts of HIV-infected individuals. Thus, we suggest that CCR5-mediated infection of LCs, and not capture of virus by LCs, provides a biologic basis for understanding certain aspects of host genetic susceptibility to initial HIV infection. Langerhans cells (LCs) are suspected to be initial targets for HIV after sexual exposure (by becoming infected or by capturing virus). Here, productive R5 HIV infection of LC ex vivo and LC-mediated transmission of virus to CD4 + T cells were both found to depend on CCR5. By contrast, infection of monocyte-derived dendritic cells and transfer of infection from monocyte-derived dendritic cells to CD4 + T cells were mediated by CCR5-dependent as well as DC-specific ICAM-3-grabbing nonintegrin-dependent pathways. Furthermore, in 62 healthy individuals, R5 HIV infection levels in LCs ex vivo were associated with CCR5 genotype. Specifically, genotyping for ORF Δ 32 revealed that LCs isolated from ORF Δ 32 / wt individuals were significantly less susceptible to HIV when compared with LCs isolated from ORFwt / wt individuals ( P = 0.016). Strikingly, further genetic analyses of the A-2459G CCR5 promoter polymorphism in ORF Δ 32 / wt heterozygous individuals revealed that LCs isolated from - 2459A / G + ORF Δ 32 / wt individuals were markedly less susceptible to HIV than were LCs from - 2459A / A + ORF Δ 32 / wt individuals ( P = 0.012). Interestingly, these genetic susceptibility data in LCs parallel those of genetic susceptibility studies performed in cohorts of HIV-infected individuals. Thus, we suggest that CCR5-mediated infection of LCs, and not capture of virus by LCs, provides a biologic basis for understanding certain aspects of host genetic susceptibility to initial HIV infection. Langerhans cells (LCs) are suspected to be initial targets for HIV after sexual exposure (by becoming infected or by capturing virus). Here, productive R5 HIV infection of LC ex vivo and LC-mediated transmission of virus to CD4 + T cells were both found to depend on CCR5. By contrast, infection of monocyte-derived dendritic cells and transfer of infection from monocyte-derived dendritic cells to CD4 + T cells were mediated by CCR5-dependent as well as DC-specific ICAM-3-grabbing nonintegrin-dependent pathways. Furthermore, in 62 healthy individuals, R5 HIV infection levels in LCs ex vivo were associated with CCR5 genotype. Specifically, genotyping for ORF Δ 32 revealed that LCs isolated from ORF Δ 32 / wt individuals were significantly less susceptible to HIV when compared with LCs isolated from ORFwt / wt individuals ( P = 0.016). Strikingly, further genetic analyses of the A-2459G CCR5 promoter polymorphism in ORF Δ 32 / wt heterozygous individuals revealed that LCs isolated from - 2459A / G + ORF Δ 32 / wt individuals were markedly less susceptible to HIV than were LCs from - 2459A / A + ORF Δ 32 / wt individuals ( P = 0.012). Interestingly, these genetic susceptibility data in LCs parallel those of genetic susceptibility studies performed in cohorts of HIV-infected individuals. Thus, we suggest that CCR5-mediated infection of LCs, and not capture of virus by LCs, provides a biologic basis for understanding certain aspects of host genetic susceptibility to initial HIV infection. Langerhans cells (LCs) are suspected to be initial targets for HIV after sexual exposure (by becoming infected or by capturing virus). Here, productive R5 HIV infection of LC ex vivo and LC-mediated transmission of virus to CD4+ T cells were both found to depend on CCR5. By contrast, infection of monocyte-derived dendritic cells and transfer of infection from monocyte-derived dendritic cells to CD4+ T cells were mediated by CCR5-dependent as well as DC-specific ICAM-3-grabbing nonintegrin-dependent pathways. Furthermore, in 62 healthy individuals, R5 HIV infection levels in LCs ex vivo were associated with CCR5 genotype. Specifically, genotyping for ORF32 revealed that LCs isolated from ORF32/wt individuals were significantly less susceptible to HIV when compared with LCs isolated from ORFwt/wt individuals (P = 0.016). Strikingly, further genetic analyses of the A-2459G CCR5 promoter polymorphism in ORF32/wt heterozygous individuals revealed that LCs isolated from -2459A/G + ORF32/wt individuals were markedly less susceptible to HIV than were LCs from -2459A/A + ORF32/wt individuals (P = 0.012). Interestingly, these genetic susceptibility data in LCs parallel those of genetic susceptibility studies performed in cohorts of HIV-infected individuals. Thus, we suggest that CCR5-mediated infection of LCs, and not capture of virus by LCs, provides a biologic basis for understanding certain aspects of host genetic susceptibility to initial HIV infection. Langerhans cells (LCs) are suspected to be initial targets for HIV after sexual exposure (by becoming infected or by capturing virus). Here, productive R5 HIV infection of LC ex vivo and LC-mediated transmission of virus to CD4+T cells were both found to depend on CCR5. By contrast, infection of monocyte-derived dendritic cells and transfer of infection from monocyte-derived dendritic cells to CD4+T cells were mediated by CCR5-dependent as well as DC-specific ICAM-3-grabbing nonintegrin-dependent pathways. Furthermore, in 62 healthy individuals, R5 HIV infection levels in LCs ex vivo were associated with CCR5 genotype. Specifically, genotyping for ORFΔ 32 revealed that LCs isolated from ORFΔ 32/wt individuals were significantly less susceptible to HIV when compared with LCs isolated from ORFwt/wt individuals (P = 0.016). Strikingly, further genetic analyses of the A-2459G CCR5 promoter polymorphism in ORFΔ 32/wt heterozygous individuals revealed that LCs isolated from -2459A/G + ORFΔ 32/wt individuals were markedly less susceptible to HIV than were LCs from -2459A/A + ORFΔ 32/wt individuals (P = 0.012). Interestingly, these genetic susceptibility data in LCs parallel those of genetic susceptibility studies performed in cohorts of HIV-infected individuals. Thus, we suggest that CCR5-mediated infection of LCs, and not capture of virus by LCs, provides a biologic basis for understanding certain aspects of host genetic susceptibility to initial HIV infection. Langerhans cells (LCs) are suspected to be initial targets for HIV after sexual exposure (by becoming infected or by capturing virus). Here, productive R5 HIV infection of LC ex vivo and LC-mediated transmission of virus to CD4 + T cells were both found to depend on CCR5. By contrast, infection of monocyte-derived dendritic cells and transfer of infection from monocyte-derived dendritic cells to CD4 + T cells were mediated by CCR5-dependent as well as DC-specific ICAM-3-grabbing nonintegrin-dependent pathways. Furthermore, in 62 healthy individuals, R5 HIV infection levels in LCs ex vivo were associated with CCR5 genotype. Specifically, genotyping for ORF Δ 32 revealed that LCs isolated from ORF Δ 32 / wt individuals were significantly less susceptible to HIV when compared with LCs isolated from ORFwt / wt individuals ( P = 0.016). Strikingly, further genetic analyses of the A-2459G CCR5 promoter polymorphism in ORF Δ 32 / wt heterozygous individuals revealed that LCs isolated from - 2459A / G + ORF Δ 32 / wt individuals were markedly less susceptible to HIV than were LCs from - 2459A / A + ORF Δ 32 / wt individuals ( P = 0.012). Interestingly, these genetic susceptibility data in LCs parallel those of genetic susceptibility studies performed in cohorts of HIV-infected individuals. Thus, we suggest that CCR5-mediated infection of LCs, and not capture of virus by LCs, provides a biologic basis for understanding certain aspects of host genetic susceptibility to initial HIV infection. Langerhans cells (LCs) are suspected to be initial targets for HIV after sexual exposure (by becoming infected or by capturing virus). Here, productive R5 HIV infection of LC ex vivo and LC-mediated transmission of virus to CD4 super(+) T cells were both found to depend on CCR5. By contrast, infection of monocyte-derived dendritic cells and transfer of infection from monocyte-derived dendritic cells to CD4 super(+) T cells were mediated by CCR5-dependent as well as DC-specific ICAM-3-grabbing nonintegrin-dependent pathways. Furthermore, in 62 healthy individuals, R5 HIV infection levels in LCs ex vivo were associated with CCR5 genotype. Specifically, genotyping for ORF[Delta]32 revealed that LCs isolated from ORF[Delta]32/wt individuals were significantly less susceptible to HIV when compared with LCs isolated from ORFwt/wt individuals (P = 0.016). Strikingly, further genetic analyses of the A-2459G CCR5 promoter polymorphism in ORF[Delta]32/wt heterozygous individuals revealed that LCs isolated from -2459A/G + ORF[Delta]32/wt individuals were markedly less susceptible to HIV than were LCs from -2459A/A + ORF[Delta]32/wt individuals (P = 0.012). Interestingly, these genetic susceptibility data in LCs parallel those of genetic susceptibility studies performed in cohorts of HIV-infected individuals. Thus, we suggest that CCR5-mediated infection of LCs, and not capture of virus by LCs, provides a biologic basis for understanding certain aspects of host genetic susceptibility to initial HIV infection. |
Author | Kawamura, Tatsuyoshi Gulden, Forrest O. Sugaya, Makoto Blauvelt, Andrew Lederman, Michael M. Zimmerman, Peter A. Borris, Debra L. Orenstein, Jan M. McNamara, David T. |
AuthorAffiliation | Dermatology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-1908; † Department of Medicine, Center for AIDS Research, Case Western Reserve University and University Hospitals, Cleveland, OH 44195; and ‡ Department of Pathology, George Washington University, Washington, DC 20037 |
AuthorAffiliation_xml | – name: Dermatology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-1908; † Department of Medicine, Center for AIDS Research, Case Western Reserve University and University Hospitals, Cleveland, OH 44195; and ‡ Department of Pathology, George Washington University, Washington, DC 20037 |
Author_xml | – sequence: 1 givenname: Tatsuyoshi surname: Kawamura fullname: Kawamura, Tatsuyoshi – sequence: 2 givenname: Forrest O. surname: Gulden fullname: Gulden, Forrest O. – sequence: 3 givenname: Makoto surname: Sugaya fullname: Sugaya, Makoto – sequence: 4 givenname: David T. surname: McNamara fullname: McNamara, David T. – sequence: 5 givenname: Debra L. surname: Borris fullname: Borris, Debra L. – sequence: 6 givenname: Michael M. surname: Lederman fullname: Lederman, Michael M. – sequence: 7 givenname: Jan M. surname: Orenstein fullname: Orenstein, Jan M. – sequence: 8 givenname: Peter A. surname: Zimmerman fullname: Zimmerman, Peter A. – sequence: 9 givenname: Andrew surname: Blauvelt fullname: Blauvelt, Andrew |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/12815099$$D View this record in MEDLINE/PubMed |
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Notes | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 Communicated by Frederick C. Robbins, Case Western Reserve University, Cleveland, OH, April 24, 2003 Abbreviations: LC, Langerhans cell; DC, dendritic cell; mDC, monocyte-derived DC; DC-SIGN, DC-specific ICAM-3-grabbing nonintegrin; SNP, single-nucleotide polymorphism; AZT, 3′-azido-3′-deoxythymidine; RANTES, regulated on activation normal T cell expressed and secreted. |
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Snippet | Langerhans cells (LCs) are suspected to be initial targets for HIV after sexual exposure (by becoming infected or by capturing virus). Here, productive R5 HIV... Langerhans cells (LCs) are suspected to be initial targets for HIV after sexual exposure (by becoming infected or by capturing virus). Here, productive R5 HIV... |
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SubjectTerms | Alleles Antibodies, Monoclonal - pharmacology Biological Sciences CCR5 Receptor Antagonists CD4 Antigens - physiology CD4-Positive T-Lymphocytes - virology Cell Adhesion Molecules - physiology Cellular biology Chemokine CCL5 - physiology Dendritic Cells - virology Endocytosis Epithelial Cells - virology Female Genetic Predisposition to Disease Genotype Genotypes Heterocyclic Compounds - pharmacology HIV HIV - physiology HIV infections HIV Infections - genetics Human immunodeficiency virus Humans Infections Langerhans Cells - physiology Langerhans Cells - virology Lectins, C-Type - physiology Male Mannans Open Reading Frames - genetics Polymorphism, Genetic Reagents Receptors, CCR5 - genetics Receptors, CCR5 - physiology Receptors, Cell Surface - physiology Receptors, CXCR4 - antagonists & inhibitors Sequence Deletion T lymphocytes Virus Replication Viruses Volunteerism |
Title | R5 HIV Productively Infects Langerhans Cells, and Infection Levels Are Regulated by Compound CCR5 Polymorphisms |
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