Insulin-Like Growth Factor 2 Receptor Is an IFNγ-Inducible Microglial Protein that Facilitates Intracellular HIV Replication

Abstract

Insulin-like growth factor 2 receptor (IGF2R), also known as cation-independent mannose 6-phosphate (M6P) receptor, is a transmembrane glycoprotein localized in the trans-Golgi region and is involved in targeting both M6P-bearing enzymes and IGF2 to the lysosomal compartment. During development, IGF2R plays a crucial role in removing excess growth factors from both tissue and blood. Due to the perinatal lethality of the global Igf2r knockout, the function of IGF2R in adults, particularly in the CNS, is not known. We made a novel observation that IGF2R is highly expressed in microglial nodules in human brains with HIV encephalitis. In vitro, microglial IGF2R expression was uniquely enhanced by IFN␥ among the several cytokines and TLR ligands examined. Furthermore, in several in vitro models of HIV infection, including human and murine microglia, macrophages, and nonmacrophage cells, IGF2R is repeatedly shown to be a positive regulator of HIV infection. IGF2R RNAi also down-regulated the production of the IP-10 chemokine in HIV-infected human microglia. Injection of VSVg env HIV into mouse brain induced HIV p24 expression in neurons, the only cell type normally expressing IGF2R in the adult brain. Our results demonstrate a novel role for IGF2R as an inducible microglial protein involved in regulation of HIV and chemokine expression. Mice with the Csf1r-driven Igf2r knockout should be useful for the investigation of macrophage-specific IGF2R function.

Insulin-like growth factor 1 and 2 (IGF1, IGF2) expression in human microglia: differential regulation by inflammatory mediators

“…Post-mortem brain sections with neuropathologic diagnosis of HIV encephalitis (HIVE) or minimal nonspecific changes (normal-appearing brains from both HIV+ and HIV− individuals) were obtained from the Manhattan HIV Brain Bank and processed for immunohistochemistry as previously described [29-31]. Briefly, sections were deparaffinized and underwent antigen retrieval in a citrate buffer at 95°C for 20 min.…”

“…IGF1, IGF2, IGFBP2, and IGFBP3 levels are also altered in individuals with HIV infection [27,28]. We have also recently reported that IGF2R is highly upregulated in HIV-infected CNS and that IGF2R is a novel IFNγ-inducible microglial protein that functions as a positive regulator of HIV infection [29]. Given these provocative findings and the significant species-dependent differences in neuroinflammatory mechanisms, we examined the regulation of IGF1 and IGF2 expression in human microglia in vivo and in vitro .…”

HIV–host interactome revealed directly from infected cells

“…In addition, we recovered receptors and modulators that affect various signalling pathways, namely, T cell receptor subunits, Notch components and Hedgehog (HHIP) as well as factors involved in calcium signalling 35,36 . HIV-1 Env also associated with the mannose-6-phosphate/insulin-like growth factor receptor 2 (ILGF2), which is thought to facilitate HIV-1 replication in microglial cells 37 . The mannose-6-phosphate modification of gp120 being host-cell-line-specific, perhaps preferentially added to the viral envelopes of transmitted founder viruses 38 .…”

The Impact of HIV Coinfection on Cerebral Malaria Pathogenesis

“…Microglial nodules seen in HIV encephalitis produce high levels of insulin-like growth factor receptor 2 (IGF2R), which is involved in intracellular HIV replication. When IGF2R expression is blocked by transfection with IGF2R siRNA, HIV production in microglia is decreased and IP-10 production is decreased [165]. …”