title: HIV-1 proteins preferentially activate anti-inflammatory M2-type macrophages.
abstract: HIV-1 proteins, including Tat, gp120, and Nef, activate macrophages (MΦ), which is consistent with the fact that HIV-1 infection is characterized by sustained immune activation. Meanwhile, MΦ are functionally classified into two types: proinflammatory M1-MΦ and anti-inflammatory M2-MΦ. We show that HIV-1 proteins, particularly Nef, preferentially activate M2-MΦ. Extracellular Tat, gp120, and Nef activated MAPK and NF-κB pathways in human peripheral blood monocyte-derived MΦ. However, the activation was marked in M-CSF-derived M2-MΦ but not GM-CSF-derived M1-MΦ. Nef was the most potent activator, and its signaling activation was comparable to that by TNF-α. Indeed, Nef was internalized more rapidly by M2-MΦ than by M1-MΦ. The myristoylation and proline-rich motif of Nef were responsible for the observed signaling activation. Consistent with the activation of MAPK/NF-κB pathways, Nef stimulated the production of a number of proinflammatory cytokines/chemokines by M2-MΦ. However, Nef reduced the expression of CD163 and phagocytosis, the characteristic markers of M2-MΦ, indicating that Nef drives an M2-like to M1-like phenotypic shift. Because the differentiation of most tissue MΦ depends on M-CSF and its receptor, which is the essential axis for the anti-inflammatory M2-MΦ phenotype, the current study reveals an efficient mechanism by which HIV-1 proteins, such as Nef, induce the proinflammatory MΦ.
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Chihara
authors.forename: Michihiro
authors.initials: M
authors.lastname: Hashimoto
authors.forename: Abu
authors.initials: A
authors.lastname: Osman
authors.forename: Yuka
authors.initials: Y
authors.lastname: Hiyoshi-Yoshidomi
authors.forename: Ikuko
authors.initials: I
authors.lastname: Suzu
authors.forename: Nopporn
authors.initials: N
authors.lastname: Chutiwitoonchai
authors.forename: Masateru
authors.initials: M
authors.lastname: Hiyoshi
authors.forename: Seiji
authors.initials: S
authors.lastname: Okada
authors.forename: Shinya
authors.initials: S
authors.lastname: Suzu
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology / Q000502:physiology*; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D008262:Macrophage Activation; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D009928:Organ Specificity; D010641:Phenotype; D061251:Primary Cell Culture; D015398:Signal Transduction; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000494:pharmacology / Q000502:physiology*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000494:pharmacology / Q000502:physiology*
chemical_list: D015415:Biomarkers; D016207:Cytokines; D015699:HIV Envelope Protein gp120; D016328:NF-kappa B; C514793:gp120 protein, Human immunodeficiency virus 1; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; D054322:tat Gene Products, Human Immunodeficiency Virus; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020929:Mitogen-Activated Protein Kinase Kinases