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Macrophage colony-stimulating factor antagonists inhibit replication of HIV-1 in human macrophages
1Division of Monoclonal Antibodies, Office of Therapeutics Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA. kutza@cber.fda.gov
Abstract:
Macrophages infected with HIV-1 produce high levels of M-CSF and macrophage-inflammatory protein-1alpha (MIP-1alpha). M-CSF facilitates the growth and differentiation of macrophages, while the chemotactic properties of MIP-1alpha attract both T lymphocytes and macrophages to the site of HIV infection. Studies described in this work indicate M-CSF may function in an autocrine/paracrine manner to sustain HIV replication, and data suggest possible therapeutic strategies for decreasing viral load following HIV infection. We show that macrophage infection with measles virus or respiratory syncytial virus, in contrast to HIV-1, results in production of MIP-1alpha, but not M-CSF. Thus, M-CSF appears to be specifically produced upon infection of macrophages with HIV-1. Furthermore, addition of M-CSF antagonists to HIV-1-infected macrophages, including anti-M-CSF monoclonal or polyclonal Abs or soluble M-CSF receptors, dramatically inhibited HIV-1 replication and reduced production of MIP-1alpha. Our results suggest that biologic antagonists for M-CSF may represent novel strategies for inhibiting the spread of HIV-1 by 1) blocking virus replication in macrophages, 2) reducing recruitment of HIV-susceptible T cells and macrophages by MIP-1alpha, and 3) preventing the establishment and maintenance of infected macrophages as a reservoir for HIV.
Insights
Macrophage colony-stimulating factor (M-CSF) fuels HIV replication and attracts immune cells. Blocking M-CSF significantly reduces HIV viral load and spread, offering a novel therapeutic strategy.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- Macrophages are key targets of HIV-1 infection.
- HIV-1 infection induces production of M-CSF and MIP-1alpha by macrophages.
- M-CSF supports macrophage proliferation and HIV replication, while MIP-1alpha recruits immune cells to infection sites.
Purpose of the Study:
- To investigate the specific role of M-CSF in HIV-1 replication within macrophages.
- To explore M-CSF antagonists as a potential therapeutic strategy against HIV-1.
Main Methods:
- Macrophages were infected with HIV-1, measles virus, or respiratory syncytial virus.
- Production of M-CSF and MIP-1alpha was measured.
- M-CSF antagonists (antibodies, soluble receptors) were added to HIV-1-infected macrophages to assess their effect on viral replication and MIP-1alpha production.
Main Results:
- HIV-1 infection specifically induced M-CSF production in macrophages, unlike other viruses.
- M-CSF antagonists significantly inhibited HIV-1 replication in macrophages.
- Treatment with M-CSF antagonists reduced MIP-1alpha production and viral spread.
Conclusions:
- M-CSF plays a critical role in sustaining HIV-1 replication and pathogenesis.
- Biologic antagonists targeting M-CSF show promise for novel HIV-1 therapies.
- Targeting M-CSF can inhibit viral replication, reduce immune cell recruitment, and prevent reservoir formation.