Triggering TLR2, -3, -4, -5, and -8 Reinforces the Restrictive Nature of M1- and M2-Polarized Macrophages to HIV

Abstract

Macrophages must react to a large number of pathogens and their effects. In chronic HIV infection, the microenvironment changes with an influx of microbial products that trigger Toll-like receptors (TLRs). That dynamic nature can be replicated ex vivo by the proinflammatory (M1-polarized) and alternatively activated (M2-polarized) macrophages. Thus, we determined how polarized macrophages primed by various TLR agonists support HIV replication. Triggering of TLR2, -3, -4, -5, and -8 reinforced the low level of permissiveness in polarized macrophages. HIV was inhibited even more in M1-polarized macrophages than in macrophages activated only by TLR agonists. HIV was inhibited before its integration into the host chromosome. Polarization and triggering by various TLR agonists resulted in distinct cytokine profiles, endocytic activity, and distinct upregulation of restriction factors of HIV. Thus, different mechanisms likely contribute to the HIV-inhibitory effects. In chronic HIV infection, macrophages might become less permissive to HIV due to changes in the microenvironment. The high level of reactivity of polarized macrophages to TLR triggering may be exploited for immunotherapeutic strategies. IMPORTANCEMacrophages are a major target of HIV-1 infection. Different cell types in this very heterogeneous cell population respond differently to stimuli. In vitro, the heterogeneity is mimicked by their polarization into proinflammatory and alternatively activated macrophages. Here we explored the extent to which agonists triggering the TLR family affect HIV replication in polarized macrophages. We found that a number of TLR agonists blocked HIV replication substantially when given before infection. We also report the mechanisms of how TLR agonists exert their inhibitory action. Our findings may advance our understanding of which and how TLR agonists block HIV infection in polarized macrophages and may facilitate the design of novel immunotherapeutic approaches.

Alterations in P-Glycoprotein Expression and Function Between Macrophage Subsets

“…There is evidence that polarized macrophages of both phenotypes, are less susceptible to infection than resting monocytes and macrophages (14). Others have suggested that early in infection M1 macrophage are permissive to infection, while the cytokine shift that occurs in late stage HIV results in a shift towards the M2 phenotype, which is resistant to infection (15).…”

Porphyromonas gingivalis-mediated signaling through TLR4 mediates persistent HIV infection of primary macrophages

“…E. coli LPS has been suggested to interfere with HIV replication at multiple steps of the HIV replication cycle in macrophages including interference of efficient viral entry (Franchin et al, 2000; Herbein et al, 1995; Herbein and Varin, 2010; Mikulak et al, 2009; Verani et al, 1997; Verani et al, 2002) and a restriction after entry but before proviral integration (Devadas et al, 2010; Donninelli et al, 2016; Pushkarsky et al, 2001; Schlaepfer et al, 2014; Wang et al, 2011). Our data suggests that a step post-proviral integration and transcription are targeted in MDMs when infected with HIV in the presence of P. gingivalis .…”

“…Furthermore, macrophages within many anatomical compartments are susceptible to direct infection by HIV-1 and this infection correlates with macrophage dysfunction including altered cytokine production, phagocytosis, pathogen killing and chemotaxis (Pugliese et al, 2005). HIV replication is dependent on the regulation of transcription factors, cytokines and anti-viral restriction factors associated with macrophage activation and the cytokine microenvironment (Cassetta et al, 2013; Cassol et al, 2009; Herbein and Varin, 2010; Koyanagi et al, 1988; Schlaepfer et al, 2014; Schuitemaker et al, 1994; Schuitemaker et al, 1992). However, it remains unclear to what extent these signals affect long term HIV pathogenesis or possibly HIV persistence.…”

Host antitumor resistance improved by the macrophage polarization in a chimera model of patients with HCC

“…37 Further, M2aMf switch to quiescent Mf in the absence of IL-4, and are reprogrammed to Mf with function to switch to M1Mf in response to TLR agonists. 43 Therefore, M2aMf exist for a relatively short time. 44 Conversely, M2bMf live longer 45 and do not require exogenous growth factors (e.g., IL-4), due to the autocrine production of CCL1, which is an essential chemokine for the maintenance of M2bMf properties.…”