title: Infection of human macrophages with an endogenous tumour necrosis factor-alpha (TNF-alpha)-independent human immunodeficiency virus type 1 isolate is unresponsive to the TNF-alpha synthesis inhibitor RP 55778.
abstract: Monocyte-derived macrophages (MDM) were demonstrated to be susceptible to productive infection by the monocytotropic human immunodeficiency virus type 1 (HIV-1) strain HIV-1/Ba-L and by three primary HIV-1 isolates, HIV-1/DAS, HIV-1/PAR and HIV-1/THI. Production of tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and IL-1 beta was monitored between days 3 and 26 after MDM infection. TNF-alpha and IL-6 were detected in cell culture supernatants from days 16 to 21 following HIV-1/DAS, HIV-1/PAR and HIV-1/Ba-L infection, at the time of high viral replication. IL-1 beta was not found at the same time points. TNF-alpha mRNA expression occurred around the peak of both TNF-alpha levels and supernatant RT activities. In HIV-1/THI-infected macrophage cultures no endogenously produced TNF-alpha was observed, despite high levels of HIV-1 in MDM. This result demonstrates that a primary isolate may replicate independently of TNF-alpha in MDM. To investigate the relationship between TNF-alpha and viral replication we used a TNF-alpha synthesis inhibitor, RP 55778. Treatment throughout the course of cell culture resulted in a significant decrease in both TNF-alpha levels and viral production in HIV-1/DAS-, HIV-1/PAR- and HIV-1/Ba-L-infected MDM cultures. This phenomenon is reversed by adding recombinant human TNF-alpha to the RP 55778-treated cell cultures from day 14 post-infection. No effect of RP 55778 was observed in MDM cultures infected with the primary isolate HIV-1/THI, whose replication is independent of TNF-alpha production and therefore remained unchanged after RP 55778 treatment. We conclude that the clinical value of such a drug is directly dependent on the ability of the HIV-1 strains involved to induce TNF-alpha production at the time of viral replication.
authors.affiliation: Laboratoire de Neuropathologie Expérimentale et Neurovirologie, CRSSA, DSV/DPTE, Institut Paris-Sud sur les Cytokines, Fontenay aux Roses, France.
authors.forename: R
authors.initials: R
authors.lastname: Le Naour
authors.forename: P
authors.initials: P
authors.lastname: Clayette
authors.forename: Y
authors.initials: Y
authors.lastname: Henin
authors.forename: A
authors.initials: A
authors.lastname: Mabondzo
authors.forename: H
authors.initials: H
authors.lastname: Raoul
authors.forename: A
authors.initials: A
authors.lastname: Bousseau
authors.forename: D
authors.initials: D
authors.lastname: Dormont
mesh_terms: D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000254:growth & development*; D006801:Humans; D016130:Immunophenotyping; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008264:Macrophages / Q000382:microbiology*; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D007375:Interleukin-1; D015850:Interleukin-6; D011725:Pyridines; D012333:RNA, Messenger; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; C052520:3-(3-pyridinyl)-1H,3H-pyrrolo(1,2-c)thiazole-7-carboxamide; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase