M1 and M2a polarization of human monocyte-derived macrophages inhibits HIV-1 replication by distinct mechanisms.
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.
Cassol
Edana
E
AIDS Immunopathogenesis Unit, Division of Immunology, San Raffaele Scientific Institute, Milan, Italy. edana.cassol@hsr.it
Cassetta
Luca
L
Rizzi
Chiara
C
Alfano
Massimo
M
Poli
Guido
G
D015704:CD4 Antigens / Q000096:biosynthesis / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000166:cytology* / Q000276:immunology / Q000821:virology*; D019713:Receptors, CCR5 / Q000096:biosynthesis / Q000276:immunology; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D014779:Virus Replication / Q000502:physiology*
D015704:CD4 Antigens; C527276:CXCR4 protein, human; D016207:Cytokines; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma