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Human astrocytes inhibit HIV-1 expression in monocyte-derived macrophages by secreted factors
1Division of Cytokine Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, MD 20852, USA.
Objective:
To determine the effects of primary human fetal and adult astrocytes on HIV-1 replication in monocyte-derived macrophages (MDM).
Design:
HIV-1 can infect the brain in the early stage of systemic infection. The HIV-1-associated cognitive/motor complex develops later in the course of the disease, suggesting that brain cells may inhibit the early productive infection and the development of neurological disease. In this study, we established an in-vitro coculture system to determine whether astrocytes can modulate HIV-1 replication in MDM.
Methods:
Elutriated human monocytes were differentiated in culture, then infected with monocyte tropic HIV-1. One day after infection, MDM were co-cultured with primary astrocytes. Reverse transcriptase (RT) activity was used to monitor virus replication. RT-polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA) and bioassay were used to assess cytokine production.
Results:
Primary human astrocytes suppressed HIV-1 replication in MDM via the production of soluble factors. Cytokine inhibitors of HIV-1, such as IFN-gamma, IL-4, IL-10 and IL-13, were not detectable, whereas transforming growth factor beta (TGF-beta) was constitutively produced only in its latent form. Paraformaldehyde-fixed astrocytes, unable to secrete cytokines, failed to inhibit HIV-1. These cells caused enhanced virus replication, however, which correlated with an increase in macrophage colony stimulating factor (M-CSF) production.
Conclusions:
Human astrocytes can increase and decrease HIV-1 expression in MDM. An imbalance between the positive and negative effects of astrocytes may contribute to the expression of virus in the brain, and the development of HIV-1-associated cognitive/motor complex.
Insights
Human astrocytes can both inhibit and promote HIV-1 replication in macrophages. Imbalances in these effects may influence HIV-1 brain expression and neurological complications.
Area of Science:
- Neuroscience
- Immunology
- Virology
Background:
- Human Immunodeficiency Virus (HIV-1) can infect the brain early in infection.
- HIV-1-associated neurological disorders develop later, suggesting potential inhibitory roles for brain cells like astrocytes.
- Astrocytes' role in modulating early HIV-1 replication in macrophages remains unclear.
Purpose of the Study:
- To investigate the effects of primary human fetal and adult astrocytes on HIV-1 replication in monocyte-derived macrophages (MDM).
- To determine if astrocytes can modulate HIV-1 replication in MDM using an in-vitro co-culture system.
Main Methods:
- Monocyte-derived macrophages (MDM) were infected with HIV-1 and co-cultured with primary astrocytes.
- HIV-1 replication was monitored by reverse transcriptase (RT) activity.
- Cytokine production was assessed using RT-polymerase chain reaction (PCR), ELISA, and bioassays.
Main Results:
- Primary human astrocytes suppressed HIV-1 replication in MDM through soluble factors.
- Transforming growth factor beta (TGF-beta) was produced in a latent form; known cytokine inhibitors were undetectable.
- Fixed astrocytes, unable to secrete cytokines, enhanced HIV-1 replication and macrophage colony-stimulating factor (M-CSF) production.
Conclusions:
- Human astrocytes exhibit dual effects on HIV-1 replication in MDM, capable of both increasing and decreasing viral expression.
- An imbalance in astrocyte-mediated positive and negative regulatory effects may contribute to HIV-1 brain pathogenesis and cognitive impairment.