M1 and M2a Polarization of Human Monocyte-Derived Macrophages Inhibits HIV-1 Replication by Distinct Mechanisms

被引:147
作者
Cassol, Edana [1 ,2 ,3 ]
Cassetta, Luca [1 ,2 ]
Rizzi, Chiara [1 ]
Alfano, Massimo [1 ]
Poli, Guido [1 ,2 ]
机构
[1] Ist Sci San Raffaele, Div Immunol Transplantat & Infect Dis, AIDS Immunopathogenesis Unit, I-20132 Milan, Italy
[2] Univ Vita Salute San Raffaele, Sch Med, Milan, Italy
[3] Univ Pretoria, MRC, Unit Inflammat & Immun, Dept Immunol,Fac Hlth Sci, ZA-0002 Pretoria, South Africa
关键词
IMMUNODEFICIENCY-VIRUS TYPE-1; INTERFERON-INDUCIBLE PROTEIN-10; TUMOR-ASSOCIATED MACROPHAGES; NECROSIS-FACTOR-ALPHA; CD4(+) T-CELLS; ANTIRETROVIRAL THERAPY; CHEMOTACTIC PROTEIN-1; CEREBROSPINAL-FLUID; CHEMOKINE MDC; ALTERNATIVE ACTIVATION;
D O I
10.4049/jimmunol.0803447
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 (M I) 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. The Journal of Immunology, 2009, 182: 6237-6246.
引用
收藏
页码:6237 / 6246
页数:10
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