Abstract
Macrophages play a crucial role in innate and adaptative immunity in response to microorganisms and are an important cellular target during HIV-1 infection. Recently, the heterogeneity of the macrophage population has been highlighted. Classically activated or type 1 macrophages (M1) induced in particular by IFN-γ display a pro-inflammatory profile. The alternatively activated or type 2 macrophages (M2) induced by Th-2 cytokines, such as IL-4 and IL-13 express anti-inflammatory and tissue repair properties. Finally IL-10 has been described as the prototypic cytokine involved in the deactivation of macrophages (dM). Since the capacity of macrophages to support productive HIV-1 infection is known to be modulated by cytokines, this review shows how modulation of macrophage activation by cytokines impacts the capacity to support productive HIV-1 infection. Based on the activation status of macrophages we propose a model starting with M1 classically activated macrophages with accelerated formation of viral reservoirs in a context of Th1 and proinflammatory cytokines. Then IL-4/IL-13 alternatively activated M2 macrophages will enter into the game that will stop the expansion of the HIV-1 reservoir. Finally IL-10 deactivation of macrophages will lead to immune failure observed at the very late stages of the HIV-1 disease.
Highlights
Macrophages (Ms) are the first line of defence of the organism against pathogens and, in response to the microenvironment, become differentially activated
The classically activated macrophages M1 are in contact with high levels of T helper 1 (Th1) cytokines (IFN-g, IL-2, IL-12), proinflammatory cytokines (TNFa, IL-1b, IL-6, IL-18) and chemokines (MIP-1a, macrophage inflammatory protein (MIP)-1b, RANTES) that favor the formation of viral reservoirs with strongly increased viral transcription and inhibition of HIV-1 entry to block superinfection within infected macrophages
Based on the activation status of macrophages we propose a model starting with M1 classically activated macrophages with accelerated formation of viral reservoirs in a context of Th1 and proinflammatory cytokines
Summary
Macrophages (Ms) are the first line of defence of the organism against pathogens and, in response to the microenvironment, become differentially activated. The classically activated macrophages M1 are in contact with high levels of Th1 cytokines (IFN-g, IL-2, IL-12), proinflammatory cytokines (TNFa, IL-1b, IL-6, IL-18) and chemokines (MIP-1a, MIP-1b, RANTES) that favor the formation of viral reservoirs with strongly increased viral transcription and inhibition of HIV-1 entry to block superinfection within infected macrophages. A M1/M2/Md macrophage polarization model and vice versa Altogether, in the lymph nodes of HIV-1-infected patients a shift from activated to deactivated macrophages throughout the disease is observed parallel to a Th1 pro-inflammatory/Th2 anti-inflammatory switch In some tissue such as the intestinal mucosal tissue, the macrophages are mostly in a deactivated stage with a local microenvironment curtailing the viral replication through the release of anti-inflammatory cytokines such as TGF-b. M1/M2/Md macrophage polarization may represent a mechanism that allows macrophages to cycle between productive and latent HIV-1 infection and vice-versa, parallel to the critical role of the tissue microenvironment which can drive the macrophage polarization either way and thereby can modulate HIV-1 replication in distinct tissues at different stages of the disease
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