title: Monocyte-lymphocyte fusion induced by the HIV-1 envelope generates functional heterokaryons with an activated monocyte-like phenotype.
abstract: Enveloped viruses induce cell-cell fusion when infected cells expressing viral envelope proteins interact with target cells, or through the contact of cell-free viral particles with adjoining target cells. CD4+T lymphocytes and cells from the monocyte-macrophage lineage express receptors for HIV envelope protein. We have previously reported that lymphoid Jurkat T cells expressing the HIV-1 envelope protein (Env) can fuse with THP-1 monocytic cells, forming heterokaryons with a predominantly myeloid phenotype. This study shows that the expression of monocytic markers in heterokaryons is stable, whereas the expression of lymphoid markers is mostly lost. Like THP-1 cells, heterokaryons exhibited FcγR-dependent phagocytic activity and showed an enhanced expression of the activation marker ICAM-1 upon stimulation with PMA. In addition, heterokaryons showed morphological changes compatible with maturation, and high expression of the differentiation marker CD11b in the absence of differentiation-inducing agents. No morphological change nor increase in CD11b expression were observed when an HIV-fusion inhibitor blocked fusion, or when THP-1 cells were cocultured with Jurkat cells expressing a non-fusogenic Env protein, showing that differentiation was not induced merely by cell-cell interaction but required cell-cell fusion. Inhibition of TLR2/TLR4 signaling by a TIRAP inhibitor greatly reduced the expression of CD11b in heterokaryons. Thus, lymphocyte-monocyte heterokaryons induced by HIV-1 Env are stable and functional, and fusion prompts a phenotype characteristic of activated monocytes via intracellular TLR2/TLR4 signaling.
authors.affiliation: Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico.
authors.forename: David
authors.initials: D
authors.lastname: Martínez-Méndez
authors.affiliation: Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Rivera-Toledo
authors.affiliation: Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico.
authors.forename: Enrique
authors.initials: E
authors.lastname: Ortega
authors.affiliation: Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico.
authors.forename: Ileana
authors.initials: I
authors.lastname: Licona-Limón
authors.affiliation: Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico. Electronic address: leonorhh@biomedicas.unam.mx.
authors.forename: Leonor
authors.initials: L
authors.lastname: Huerta
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology; D002459:Cell Fusion; D002478:Cells, Cultured; D006801:Humans; D016130:Immunophenotyping; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D019169:Jurkat Cells; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D054299:env Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D002273:Carcinogens; D054299:env Gene Products, Human Immunodeficiency Virus; D018799:Intercellular Adhesion Molecule-1; D013755:Tetradecanoylphorbol Acetate
keywords: Cell-cell fusion; HIV envelope protein; Heterokaryons; Monocyte differentiation; Multinucleated cells; TLR