title: Enhanced human immunodeficiency virus infection in macrophages by high-molecular-weight dextran sulfate is associated with conformational changes of gp120 and expression of the CCR5 receptor.
abstract: High-molecular-weight dextran sulfate (HMDS) inhibits infection of CD4+ lymphocytes by T-cell (T)-tropic human immunodeficiency virus (HIV) isolates, but augments replication of macrophage (M)-tropic isolates in primary human macrophages and phorbol myristate acetate (PMA)-differentiated THP-1 monocytic cells. To address the mechanism responsible for HMDS-mediated increases in HIV replication in macrophages, we analyzed the interaction between HMDS and functional domains of gp120 on the surface of PMA-differentiated THP-1 cells infected with M-tropic HIV isolates. Immunofluorescence staining of the infected cells revealed that HMDS inhibited the binding of monoclonal antibodies (mAbs) directed to the V3 and C4 domains of gp120, but augmented the binding of three neutralizing antibodies directed to the V2 region of gp120. The extent of HMDS-mediated changes within the V2 loop of gp120 was associated with increased virus binding and replication in PMA-differentiated THP-1 cells and primary macrophages. The effect was dependent on expression of the CCR5 receptor and was inhibited by the beta-chemokine RANTES. Results of this study suggest that HMDS-mediated increases in HIV infection in macrophages are associated with conformational changes within the V2 region of gp120 and enhanced interaction between gp120 and the CCR5 coreceptor on the target cell.
authors.affiliation: Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: P P
authors.initials: PP
authors.lastname: Jagodzinski
authors.forename: A
authors.initials: A
authors.lastname: Wierzbicki
authors.forename: J
authors.initials: J
authors.lastname: Wustner
authors.forename: Y
authors.initials: Y
authors.lastname: Kaneko
authors.forename: D
authors.initials: D
authors.lastname: Kozbor
mesh_terms: D002460:Cell Line; D016264:Dextran Sulfate / Q000378:metabolism / Q000494:pharmacology*; D005434:Flow Cytometry; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000821:virology*; D008970:Molecular Weight; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D011487:Protein Conformation / Q000187:drug effects; D019713:Receptors, CCR5 / Q000096:biosynthesis*; D014779:Virus Replication / Q000276:immunology
chemical_list: D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5; D016264:Dextran Sulfate