Trained Immunity and HIV Infection

Abstract

Findings that certain infections induce immunity not only against the causing agent, but also against an unrelated pathogen have intrigued investigators for many years. Recently, underlying mechanisms of this phenomenon have started to come to light. It was found that the key cells responsible for heterologous protection are innate immune cells such as natural killer cells (NKs), dendritic cells, and monocytes/macrophages. These cells are 'primed' by initial infection, allowing them to provide enhanced response to subsequent infection by the same or unrelated agent. This phenomenon of innate immune memory was termed 'trained immunity'. The proposed mechanism for trained immunity involves activation by the first stimulus of metabolic pathways that lead to epigenetic changes, which maintain the cell in a "trained" state, allowing enhanced responses to a subsequent stimulus. Innate immune memory can lead either to enhanced responses or to suppression of subsequent responses ('tolerance'), depending on the strength and length of the initial stimulation of the immune cells. In the context of HIV infection, innate memory induced by infection is not well understood. In this Hypothesis and Theory article, we discuss evidence for HIV-induced trained immunity in human monocytes, its possible mechanisms, and implications for HIV-associated co-morbidities.

Keywords: HIV-1; Nef; co-morbidities; exosomes; inflammation; lipid rafts; trained immunity.

Figure 1

Proposed model of trained immunity induced by exNef. The figure shows suggested sequence of events occurring when monocyte encounters Nef-containing extracellular vesicle (exNef). ExNef induces proteasomal degradation of plasma membrane ABCA1, modifying lipid rafts and increasing their abundance. Lipid raft changes promote dimerization and activation of TLR4 (TLR4* in the figure), which sends activating signal to inflammatory genes. Additionally, exNef stimulates glycolysis and cholesterol biosynthesis. One of the intermediate products of glycolysis, fumarate, is a negative regulator of the KDM5 histone demethylase, inhibition of which promotes trimethylation of the H3 histone on the K4 residue (H3K4me3). Another product of glycolysis, citrate, stimulates synthesis of Acetyl-CoA, which is a positive regulator of histone acetyltransferase and promotes acetylation of the H3 histone on the K27 residue (H3K27ac). Both modifications are associated with transcriptionally active chromatin. These events lead to epigenetic modifications resulting in sustained changes in lipid rafts and inflammatory cytokine production. ExNef also suppress ABCA1 maturation and delivery to plasma membrane, resulting in decreased ABCA1 and suppressed cholesterol efflux. The cell becomes enriched in cholesterol, and the abundance of lipid rafts further increases, exacerbating events described above. An intermediate product of cholesterol biosynthesis, mevalonate, is secreted from the cell and stimulates the IGF1R, whose representation is increased on overabundant lipid rafts. Signaling from IGF1R stimulates the Akt-mTOR pathway, which further potentiates epigenetic remodeling. Histone modifications alter expression of lipid raft regulating proteins (ABCA1 is shown as an example, switching from active to suppressed state) and pro-inflammatory cytokines (IL-6 and TNF switch from suppressed to active state). Epigenetic changes in lipid raft regulating genes ensure persistent ‘activation’ of the lipid rafts, whereas epigenetic modifications of cytokine genes lead to overreaction to inflammatory stimuli. Together, these two mechanisms synergize to promote inflammation.