M1 and M2a polarization of human monocyte-derived macrophages inhibits HIV-1 replication by distinct mechanisms

Edana Cassol, Luca Cassetta, Chiara Rizzi, Massimo Alfano, Guido Poli

Research output: Contribution to journalArticlepeer-review


The capacity of macrophages to support productive HIV-1 infection is known to be modulated by cytokines and other extracellular stimuli. In this study, we demonstrate that cytokine-induced polarization of human monocyte-derived macrophage (MDM) into either classical (M1) or alternatively activated (M2a) MDM is associated with a reduced capacity to support productive CCR5-dependent (R5) HIV-1 infection. M1 polarization was associated with a significant down-regulation of CD4 receptors, increased secretion of CCR5-binding chemokines (CCL3, CCL4, and CCL5), and a >90% decrease in HIV-1 DNA levels 48-h postinfection, suggesting that the inhibition occurred at an early preintegration step in the viral life cycle. In contrast, M2a polarization had no effect on either HIV-1 DNA or protein expression levels, indicating that inhibition occurred at a late/postintegration level in the viral life cycle. M2a inhibition was sustained for up to 72-h postinfection, whereas M1-effects were more short-lived. Most phenotypic and functional changes were fully reversible 7 days after removal of the polarizing stimulus, and a reciprocal down-regulation of M1-related chemokines and cytokines was observed in M2a MDM and vice versa. Since reversion to a nonpolarized MDM state was associated with a renewed capacity to support HIV replication to control levels, M1/M2a polarization may represent a mechanism that allows macrophages to cycle between latent and productive HIV-1 infection.

Original languageEnglish
Pages (from-to)6237-46
Number of pages10
JournalThe Journal of Immunology
Issue number10
Publication statusPublished - 15 May 2009


  • CD4 Antigens/biosynthesis
  • Cell Differentiation/immunology
  • Cytokines/biosynthesis
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • HIV Infections/immunology
  • HIV-1/physiology
  • Humans
  • Interferon-gamma/immunology
  • Macrophage Activation/immunology
  • Macrophages/cytology
  • Receptors, CCR5/biosynthesis
  • Receptors, CXCR4/biosynthesis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Necrosis Factor-alpha/immunology
  • Virus Replication/physiology


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