title: Maximal HIV-1 replication in alveolar macrophages during tuberculosis requires both lymphocyte contact and cytokines.
abstract: HIV-1 replication is markedly upregulated in alveolar macrophages (AM) during pulmonary tuberculosis (TB). This is associated with loss of an inhibitory CCAAT enhancer binding protein beta (C/EBPbeta) transcription factor and activation of nuclear factor (NF)-kappaB. Since the cellular immune response in pulmonary TB requires lymphocyte--macrophage interaction, a model system was developed in which lymphocytes were added to AM. Contact between lymphocytes and AM reduced inhibitory C/EBPbeta, activated NF-kappaB, and enhanced HIV-1 replication. If contact between lymphocytes and macrophages was prevented, inhibitory C/EBPbeta expression was maintained and the HIV-1 long terminal repeat (LTR) was not maximally stimulated although NF-kappaB was activated. Antibodies that cross-linked macrophage expressed B-7, and vascular cell adhesion molecule and CD40 were used to mimic lymphocyte contact. All three cross-linking antibodies were required to abolish inhibitory C/EBPbeta expression. However, the HIV-1 LTR was not maximally stimulated and NF-kappaB was not activated. Maximal HIV-1--LTR stimulation required both lymphocyte-derived soluble factors, and cross-linking of macrophage expressed costimulatory molecules. High level HIV-1--LTR stimulation was also achieved when IL-1beta, IL-6, and TNF-beta were added to macrophages with cross-linked costimulatory molecules. Contact between activated lymphocytes and macrophages is necessary to down-regulate inhibitory C/EBPbeta, thereby derepressing the HIV-1 LTR. Lymphocyte-derived cytokines activate NF-kappaB, further enhancing the HIV-1 LTR.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Hoshino
authors.forename: Koh
authors.initials: K
authors.lastname: Nakata
authors.forename: Satomi
authors.initials: S
authors.lastname: Hoshino
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Honda
authors.forename: Doris B
authors.initials: DB
authors.lastname: Tse
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Shioda
authors.forename: William N
authors.initials: WN
authors.lastname: Rom
authors.forename: Michael
authors.initials: M
authors.lastname: Weiden
mesh_terms: D015153:Blotting, Western; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002448:Cell Adhesion; D016207:Cytokines / Q000276:immunology* / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D015658:HIV Infections / Q000150:complications / Q000276:immunology / Q000821:virology; D016325:HIV Long Terminal Repeat / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D008213:Lymphocyte Activation; D016676:Macrophages, Alveolar / Q000166:cytology* / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D014376:Tuberculosis / Q000150:complications / Q000276:immunology / Q000821:virology*; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D016207:Cytokines; D016328:NF-kappa B