HIV-1 proteins preferentially activate anti-inflammatory M2-type macrophages

J Immunol. 2012 Apr 15;188(8):3620-7. doi: 10.4049/jimmunol.1101593. Epub 2012 Mar 9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers / metabolism
  • Cell Differentiation
  • Cytokines / biosynthesis
  • Cytokines / immunology
  • Gene Expression Regulation
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • HIV Envelope Protein gp120 / pharmacology
  • HIV Envelope Protein gp120 / physiology*
  • HIV Infections / immunology
  • HIV Infections / virology
  • HIV-1 / immunology*
  • Humans
  • Inflammation / immunology
  • Inflammation / pathology
  • Macrophage Activation
  • Macrophage Colony-Stimulating Factor / pharmacology
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Mitogen-Activated Protein Kinase Kinases / genetics
  • Mitogen-Activated Protein Kinase Kinases / immunology
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • Organ Specificity
  • Phenotype
  • Primary Cell Culture
  • Signal Transduction
  • nef Gene Products, Human Immunodeficiency Virus / pharmacology
  • nef Gene Products, Human Immunodeficiency Virus / physiology*
  • tat Gene Products, Human Immunodeficiency Virus / pharmacology
  • tat Gene Products, Human Immunodeficiency Virus / physiology*

Substances

  • Biomarkers
  • Cytokines
  • HIV Envelope Protein gp120
  • NF-kappa B
  • gp120 protein, Human immunodeficiency virus 1
  • nef Gene Products, Human Immunodeficiency Virus
  • nef protein, Human immunodeficiency virus 1
  • tat Gene Products, Human Immunodeficiency Virus
  • Macrophage Colony-Stimulating Factor
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Mitogen-Activated Protein Kinase Kinases