title: Preferential coreceptor utilization and cytopathicity by dual-tropic HIV-1 in human lymphoid tissue ex vivo.
abstract: Many HIV-1 isolates at the late stage of disease are capable of using both CXCR4 and CCR5 in transfected cell lines, and are thus termed dual-tropic. Here we asked whether these dual-tropic variants also use both coreceptors for productive infection in a natural human lymphoid tissue microenvironment, and whether use of a particular coreceptor is associated with viral cytopathicity. We used 3 cloned dual-tropic HIV-1 variants, 89.6 and its chimeras 89-v345.SF and 89-v345.FL, which use both CCR5 and CXCR4 in transfected cell lines. In human lymphoid tissue ex vivo, one variant preferentially used CCR5, another preferentially used CXCR4, and a third appeared to be a true dual-tropic variant. The 2 latter variants severely depleted CD4(+) T cells, whereas cytopathicity of the virus that used CCR5 only in lymphoid tissue was mild and confined to CCR5(+)/CD4(+) T cells. Thus, (a) HIV-1 coreceptor usage in vitro cannot be unconditionally extrapolated to natural microenvironment of human lymphoid tissue; (b) dual-tropic viruses are not homogeneous in their coreceptor usage in lymphoid tissue, but probably comprise a continuum between the 2 polar variants that use CXCR4 or CCR5 exclusively; and (c) cytopathicity toward the general CD4(+) T cell population in lymphoid tissue is associated with the use of CXCR4.
authors.affiliation: Laboratory of Molecular and Cellular Biophysics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: S
authors.initials: S
authors.lastname: Glushakova
authors.forename: Y
authors.initials: Y
authors.lastname: Yi
authors.forename: J C
authors.initials: JC
authors.lastname: Grivel
authors.forename: A
authors.initials: A
authors.lastname: Singh
authors.forename: D
authors.initials: D
authors.lastname: Schols
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: R G
authors.initials: RG
authors.lastname: Collman
authors.forename: L
authors.initials: L
authors.lastname: Margolis
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology; D001596:Benzylamines; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000494:pharmacology; D018925:Chemokines / Q000502:physiology; D018920:Coculture Techniques; D000080027:Cyclams; D003588:Cytopathogenic Effect, Viral; D015752:Genes, env; D016655:HIV Core Protein p24 / Q000096:biosynthesis; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015497:HIV-1 / Q000145:classification / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D008213:Lymphocyte Activation; D046911:Macromolecular Substances; D008264:Macrophages / Q000821:virology; D008561:Membrane Fusion; D008954:Models, Biological; D009928:Organ Specificity; D014066:Palatine Tonsil / Q000166:cytology / Q000821:virology; D019713:Receptors, CCR5 / Q000187:drug effects / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000187:drug effects / Q000378:metabolism*; D015728:Receptors, HIV / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000821:virology; D014162:Transfection; D014774:Virulence
chemical_list: D019380:Anti-HIV Agents; D001596:Benzylamines; D018946:Chemokine CCL5; D018925:Chemokines; D000080027:Cyclams; D016655:HIV Core Protein p24; D015699:HIV Envelope Protein gp120; D006571:Heterocyclic Compounds; D046911:Macromolecular Substances; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D015728:Receptors, HIV; C088327:plerixafor