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: R Le Naour, P Clayette, Y Henin, A Mabondzo, H Raoul, A Bousseau, D Dormont
• Journal: The Journal of general virology (J Gen Virol) Vol. 75 ( Pt 6) Pg. 1379-88 (Jun 1994) ISSN: 0022-1317 [Print] England
• PMID: 7515938 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-1
• Interleukin-6
• Pyridines
• RNA, Messenger
• Thiazoles
• Tumor Necrosis Factor-alpha
• 3-(3-pyridinyl)-1H,3H-pyrrolo(1,2-c)thiazole-7-carboxamide
• HIV Reverse Transcriptase
• RNA-Directed DNA Polymerase

Topics

• Cells, Cultured
• Gene Expression (drug effects)
• HIV Reverse Transcriptase
• HIV-1 (growth & development)
• Humans
• Immunophenotyping
• In Vitro Techniques
• Interleukin-1 (biosynthesis)
• Interleukin-6 (biosynthesis)
• Macrophages (microbiology)
• Pyridines (pharmacology)
• RNA, Messenger (genetics)
• RNA-Directed DNA Polymerase (metabolism)
• Thiazoles (pharmacology)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, biosynthesis, pharmacology)
• Virus Replication (drug effects)