Abstract
HIV infection has a profound effect on “bystander” cells causing metabolic co-morbidities. This may be mediated by exosomes secreted by HIV-infected cells and containing viral factors. Here we show that exosomes containing HIV-1 protein Nef (exNef) are rapidly taken up by macrophages releasing Nef into the cell interior. This caused down-regulation of ABCA1, reduction of cholesterol efflux and sharp elevation of the abundance of lipid rafts through reduced activation of small GTPase Cdc42 and decreased actin polymerization. Changes in rafts led to re-localization of TLR4 and TREM-1 to rafts, phosphorylation of ERK1/2, activation of NLRP3 inflammasome, and increased secretion of pro-inflammatory cytokines. The effects of exNef on lipid rafts and on inflammation were reversed by overexpression of a constitutively active mutant of Cdc42. Similar effects were observed in macrophages treated with exosomes produced by HIV-infected cells or isolated from plasma of HIV-infected subjects, but not with exosomes from cells and subjects infected with ΔNef-HIV or uninfected subjects. Mice injected with exNef exhibited monocytosis, reduced ABCA1 in macrophages, increased raft abundance in monocytes and augmented inflammation. Thus, Nef-containing exosomes potentiated pro-inflammatory response by inducing changes in cholesterol metabolism and reorganizing lipid rafts. These mechanisms may contribute to HIV-associated metabolic co-morbidities.
Highlights
HIV productively infects CD4+ T-cells, macrophages and related cells expressing CD4 receptor and CCR5 or CXCR4 co-receptors, but not other cell types that lack these molecules, and cannot replicate in tissues where susceptible cells are underrepresented
Macrophages, which are involved in pathogenesis of atherosclerosis, can be infected by HIV, the proportion of infected monocytes in blood and macrophages in tissues of ARTtreated patients is too low to be a major driver of systemic atherosclerosis
We investigated the effect of Nef-containing exosomes on uninfected macrophages and identified the mechanism that may play a key role in pathogenesis of several metabolic co-morbidities of HIV infection
Summary
HIV productively infects CD4+ T-cells, macrophages and related cells expressing CD4 receptor and CCR5 or CXCR4 co-receptors, but not other cell types that lack these molecules, and cannot replicate in tissues where susceptible cells are underrepresented. Nef (Negative Regulatory Factor), for example, is known to affect tissues through cytotoxicity, and other HIV proteins released from infected host cells may contribute to the systemic effects of the infection in various ways [6]. These effects can take place even in the context of effective anti-retroviral treatment due to ongoing expression of HIV proteins in long-living infected cells and HIV replication in viral reservoirs [5, 7]. Nef was found in blood of HIV-infected patients receiving ART [8, 9]
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