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 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.
Kawamura
Tatsuyoshi
T
Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1908, USA.
Gulden
Forrest O
FO
Sugaya
Makoto
M
McNamara
David T
DT
Borris
Debra L
DL
Lederman
Michael M
MM
Orenstein
Jan M
JM
Zimmerman
Peter A
PA
Blauvelt
Andrew
A
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001596:Benzylamines; D065100:CCR5 Receptor Antagonists; D015704:CD4 Antigens / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D015815:Cell Adhesion Molecules / Q000502:physiology; D018946:Chemokine CCL5 / Q000502:physiology; D000080027:Cyclams; D003713:Dendritic Cells / Q000821:virology; D004705:Endocytosis; D004847:Epithelial Cells / Q000821:virology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006678:HIV / Q000502:physiology*; D015658:HIV Infections / Q000235:genetics; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D007801:Langerhans Cells / Q000502:physiology / Q000821:virology*; D037181:Lectins, C-Type / Q000502:physiology; D008297:Male; D016366:Open Reading Frames / Q000235:genetics; D011110:Polymorphism, Genetic; D019713:Receptors, CCR5 / Q000235:genetics / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors; D011956:Receptors, Cell Surface / Q000502:physiology; D017384:Sequence Deletion; D014779:Virus Replication; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D000911:Antibodies, Monoclonal; D001596:Benzylamines; D065100:CCR5 Receptor Antagonists; D015704:CD4 Antigens; D015815:Cell Adhesion Molecules; D018946:Chemokine CCL5; D000080027:Cyclams; D006571:Heterocyclic Compounds; D037181:Lectins, C-Type; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C088327:plerixafor