title: Macrophage colony-stimulating factor antagonists inhibit replication of HIV-1 in human macrophages.
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.
authors.affiliation: Division 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
authors.forename: J
authors.initials: J
authors.lastname: Kutza
authors.forename: L
authors.initials: L
authors.lastname: Crim
authors.forename: S
authors.initials: S
authors.lastname: Feldman
authors.forename: M P
authors.initials: MP
authors.lastname: Hayes
authors.forename: M
authors.initials: M
authors.lastname: Gruber
authors.forename: J
authors.initials: J
authors.lastname: Beeler
authors.forename: K A
authors.initials: KA
authors.lastname: Clouse
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000998:Antiviral Agents / Q000502:physiology*; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D006041:Goats; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D019402:Macrophage Inflammatory Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D051379:Mice; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000502:physiology; D014779:Virus Replication / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D000998:Antiviral Agents; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D007106:Immune Sera; D019402:Macrophage Inflammatory Proteins; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor