Regulation of HIV1 replication in promonocytic U937 cells.
Viral infection of immunocompetent cells always leads to disordered regulation of the immune system. Thus, infection by HIV1 (human immunodeficiency virus, type 1) of mononuclear phagocytes and lymphocytes is linked to the induction of the acquired immunodeficiency syndrome (AIDS). HIV1 replication in mononuclear phagocytes appears to be dependent on both the stage of maturation and on differentiation of mononuclear phagocytes. Because of the heterogeneity of the mononuclear phagocyte system, the U937 cell line provides a convenient model for studying the regulation of HIV1 replication in mononuclear phagocytes and the involvement of these cells in the immunopathogenesis of HIV1. We have shown that endogenous interferon alpha (IFN alpha) restricted viral replication in these promonocytic cells, probably by acting on proviral transcription and by interfering with transcriptional factors involved in the transactivation of the LTR (long terminal repeat) of HIV1. Indeed, addition of a monoclonal antibody to IFN alpha U937 cells cotransfected with a LTR HIV linked to the bacterial chloramphenicol acetyl transferase (CAT) gene, together with a tat expression vector, leads to an increase in CAT activity. Conversely, the addition of IFN alpha to cells cotransfected with the same vectors is followed by a decrease in CAT activity. Finally, recent experiments indicate that chronically HIV-1-infected U937 cells are more differentiated than uninfected U937 cells, suggesting that viral gene expression is able to trigger the maturation process of the promonocytic cells towards a stage where viral transcription may escape IFN alpha. These results suggest that the first replicative cycle of HIV1 in monocytes/macrophages could be a unique target for therapeutic strategies based on the use of IFN alpha.
Gazzolo
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Laboratoire d'Immuno-Virologie Moléculaire et Cellulaire, UMR 30 CNRS/UCBL, Faculté de Médecine Alexis Carrel, Lyon, France.
Macé
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D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics; D002448:Cell Adhesion; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000254:growth & development*; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology; D010586:Phagocytes / Q000187:drug effects / Q000276:immunology / Q000382:microbiology*; D011401:Promoter Regions, Genetic; D013234:Stem Cells / Q000382:microbiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014775:Virus Activation; D014779:Virus Replication / Q000187:drug effects
D007370:Interferon Type I; D015500:Chloramphenicol O-Acetyltransferase