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M1 and M2a Polarization of Human Monocyte-Derived Macrophages Inhibits HIV-1 Replication by Distinct Mechanisms¹

Edana Cassol^2,*,,, Luca Cassetta^*,, Chiara Rizzi^*, Massimo Alfano^* and Guido Poli^*,

^* AIDS Immunopathogenesis Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, School of Medicine, Milan, Italy; and Medical Research Council Unit of Inflammation and Immunity, Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ The work was supported in part by the FP6 EU Grant, Europrise (to G.P.).

² Address correspondence and reprint requests to Dr. Edana Cassol, P2/P3 Laboratories, DIBIT, Via Olgettina n. 58, 20132 Milan, Italy. E-mail address: edana.cassol{at}hsr.it

³ Abbreviations used in this paper: MDM, monocyte-derived macrophage; IL-1ra, IL-1 receptor antagonist; MFI, mean fluorescence intensity; NHS, normal human serum; RT, reverse transcriptase.