R5 HIV productively infects Langerhans cells, and infection levels are regulated by compoundCCR5polymorphisms

• DOI: 10.1073/pnas.1432450100
• Publication Date: 2003-07-08T19:18:15Z
• Authors: Tatsuyoshi Kawamura; Forrest O. Gulden; Makoto Sugaya; David T. McNamara; Debra L. Borris; Michael M. Lederman; Jan M. Orenstein; Peter A. Zimmerman; Andrew Blauvelt
• Keywords: CD4-Positive T-Lymphocytes; Benzylamines; 0303 health sciences; Genotype; Antibodies, Monoclonal; HIV; Epithelial Cells; HIV Infections; Dendritic Cells; Cyclams; Endocytosis; 3. Good health; 03 medical and health sciences; Heterocyclic Compounds; Langerhans Cells; CCR5 Receptor Antagonists; CD4 Antigens; Humans; Female; Genetic Predisposition to Disease; Lectins, C-Type; Cell Adhesion Molecules; Chemokine CCL5

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 LCex vivoand 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 LCsex vivowere associated withCCR5genotype. Specifically, genotyping forORFΔ32revealed that LCs isolated fromORFΔ32/wtindividuals were significantly less susceptible to HIV when compared with LCs isolated fromORFwt/wtindividuals (P= 0.016). Strikingly, further genetic analyses of theA-2459G CCR5promoter polymorphism inORFΔ32/wtheterozygous individuals revealed that LCs isolated from -2459A/G+ORFΔ32/wtindividuals were markedly less susceptible to HIV than were LCs from -2459A/A+ORFΔ32/wtindividuals (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.