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Interferon-gamma-activated monocytes impair infectivity of HIV particles by an oxygen metabolite-dependent reaction
Abstract:
Mononuclear phagocytes generate microbicidal oxygen metabolites spontaneously and after phagocytic stimulation by a NADPH-dependent enzymatic reaction called the oxidative burst. The spontaneous release of reactive oxygen radicals and intermediates (ROI) increases five- to eightfold after treatment of monocytes with the lymphokine interferon-gamma (IFN-gamma). The effect of the IFN-gamma-activated release of ROI by human monocytes on the infectivity of free human immunodeficiency virus (HIV) in the supernatant was investigated with the following results. First, IFN-gamma-activated, but neither control monocytes nor lipopolysaccharide-stimulated monocytes effectively decreased the infectivity of cell-free HIV-1 in culture medium supernatant. Second, the mechanism of inactivation was dependent on the enhanced spontaneous release of ROI by IFN-gamma-activated mononuclear phagocytes, since either the enzyme catalase or the free radical scavenger butylated hydroxyanisole (BHA) could block this activity. Third, soluble and solid-phase HIV-1 outer envelope glycoprotein (gp120) failed to trigger the oxidative burst activity after specific gp120-monocytic CD4 receptor interaction. These results indicate an anti-viral effect of IFN-gamma-activated monocytes/macrophages on HIV-1 which may have important implications for our understanding of spread of the virus in the body and the development of full-blown AIDS after a long period of latency.
Insights
Interferon-gamma (IFN-gamma) activates monocytes to release reactive oxygen intermediates (ROI), which effectively reduce human immunodeficiency virus (HIV) infectivity. This antiviral effect is mediated by enhanced spontaneous ROI release, not by direct interaction with HIV envelope proteins.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- Mononuclear phagocytes produce microbicidal reactive oxygen intermediates (ROI) via the NADPH-dependent oxidative burst.
- Interferon-gamma (IFN-gamma) significantly enhances spontaneous ROI release from monocytes.
- Understanding mechanisms controlling human immunodeficiency virus (HIV) spread is crucial for AIDS pathogenesis.
Purpose of the Study:
- To investigate the impact of IFN-gamma-activated human monocyte ROI release on cell-free HIV infectivity.
- To elucidate the mechanism by which IFN-gamma-activated monocytes affect HIV infectivity.
- To determine if HIV envelope glycoprotein (gp120) interaction with CD4 receptors triggers monocyte oxidative burst.
Main Methods:
- Treatment of human monocytes with IFN-gamma and lipopolysaccharide.
- Measurement of spontaneous and stimulated reactive oxygen intermediate (ROI) release.
- Assay of cell-free HIV-1 infectivity in monocyte culture supernatants.
- Inhibition studies using catalase and butylated hydroxyanisole (BHA).
Main Results:
- IFN-gamma-activated monocytes, but not control or LPS-stimulated monocytes, significantly reduced HIV-1 infectivity in supernatant.
- The antiviral activity was dependent on enhanced spontaneous ROI release, as catalase and BHA blocked inactivation.
- HIV-1 gp120 failed to induce oxidative burst activity upon CD4 receptor interaction.
Conclusions:
- IFN-gamma-activated monocytes/macrophages exhibit an antiviral effect against HIV-1.
- This anti-HIV activity is mediated by enhanced spontaneous release of reactive oxygen intermediates.
- Findings suggest a potential role for IFN-gamma-modulated innate immunity in controlling HIV spread and AIDS development.