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Recombinant interleukin 4 stimulates human immunodeficiency virus production by infected monocytes and macrophages
F Kazazi1, J M Mathijs, J Chang
1Department of Virology, Westmead Hospital, Sydney, New South Wales, Australia.
Insights
Interleukin 4 (IL-4) significantly boosts human immunodeficiency virus (HIV) production in monocytes and macrophages. This cytokine enhances viral replication and may promote HIV transmission through aggregate formation.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- Interleukin 4 (IL-4) is a cytokine with pleiotropic effects on immune cells.
- Human immunodeficiency virus (HIV) infects monocytes and macrophages, key cells in the innate and adaptive immune systems.
- Understanding host factors that modulate HIV replication is crucial for developing therapeutic strategies.
Purpose of the Study:
- To investigate the effect of recombinant interleukin 4 (IL-4) on human immunodeficiency virus (HIV) production in human monocytes and macrophages.
- To determine if IL-4 influences the proportion of HIV-infected cells and viral RNA levels.
- To explore the potential role of IL-4 in HIV transmission.
Main Methods:
- Human blood-derived monocytes and macrophages were infected with various monocytotropic HIV strains.
- Cells were incubated with recombinant IL-4 after virus inoculation.
- HIV production was assessed by measuring extracellular and intracellular viral antigens, reverse transcriptase activity, and TCID50 assays.
- In situ hybridization and semi-quantitative hybridization were used to determine the proportion of infected cells and intracellular HIV RNA levels.
- Antibody to IL-4 was used to block the cytokine's effect.
Main Results:
- Recombinant IL-4 significantly stimulated both extracellular and intracellular HIV production in monocytes and macrophages when added after virus inoculation.
- The stimulatory effect was observed in a majority of experiments with both cell types and various HIV strains.
- IL-4 increased the proportion of HIV-infected monocytes and macrophages, particularly in macrophages where infection rates rose from 35-45% to 66-70%.
- IL-4 treatment led to increased intracellular HIV RNA levels and enhanced formation of viral aggregates, suggesting increased viral replication and potential for transmission.
- Antibody to IL-4 neutralized the observed stimulatory effect.
Conclusions:
- Interleukin 4 (IL-4) acts as a potent stimulator of human immunodeficiency virus (HIV) replication in early-phase infection of monocytes and macrophages.
- IL-4 enhances viral production, increases the number of infected cells, and promotes viral RNA accumulation.
- The findings suggest that IL-4 may play a role in facilitating HIV transmission, potentially through the formation of viral aggregates.
Abstract:
Recombinant interleukin 4 (IL-4) stimulated extracellular (EC) and intracellular (IC) production of human immunodeficiency virus (HIV) from infected human blood-derived monocytes and macrophages when incubated with the cells after but not before virus inoculation. Significant stimulation was observed in 20 of 27 experiments with monocytes (inoculated with HIV immediately after adherence) and 10 of 13 experiments with macrophages (inoculated after 5 days adherence) using a total of 30 normal donors of monocytes and macrophages, and 11 recent isolates of monocytotropic HIV strains (after one passage in mononuclear cells). Marked increases in EC and IC HIV antigen were observed in some experiments, which were comparable with the maximal stimulatory effects of other cytokines such as IL-2. IL-4 also had similar effects on infectious HIV concentration as measured by reverse transcriptase and TCID50 assays. Antibody to IL-4 prevented the stimulatory effect of the cytokine. The proportion of monocytes and macrophages infected by HIV, as determined by in situ hybridization, also increased after incubation with IL-4 for 7 days. The most marked effects were observed with HIV-infected macrophages, for which the proportion of unstimulated infected cells was lower (35 to 45% increasing to 66 to 70% with IL-4 treatment). There was also an increased proportion of cells with high granule concentrations, suggesting that IL-4 increases the intracellular concentration of viral nucleic acids. This was supported by semi-quantitative hybridization experiments showing that total HIV RNA increased in IL-4-stimulated monocytes 48 to 96 h after HIV inoculation. A marked increase in aggregates was observed on day 7 in HIV-infected monocytes treated with IL-4, compared to that in HIV-infected cells alone or IL-4-treated uninfected monocytes. These findings suggest that IL-4 stimulates HIV replication in the early phases of infection and may also facilitate virus transmission by aggregate formation.