Lipids at the interface of virus-host interactions

Abstract

Viruses physically and metabolically remodel the host cell to establish an optimal environment for their replication. Many of these processes involve the manipulation of lipid signaling, synthesis, and metabolism. An emerging theme is that these lipid-modifying pathways are also linked to innate antiviral responses and can be modulated to inhibit viral replication.

Figure 1. Roles for lipids in viral replication compartment formation

A. Lipid synthesis. Flaviviruses recruit lipid synthesis machinery to expand surface area of membranes to accommodate replication machinery. Specific example of lipids enriched in DENV replication compartments is shown [15*]. In addition to general lipid synthesis, membrane fluidity is either reduced by enrichment of cholesterol and sphingomyelin in certain domains, while unsaturated phospholipids are enhanced to increase fluidity in other areas of replication compartments. Membrane curving lipids such as ceramide that induces negative curvature and lysophosphatidylcholine (Lyso PC) that induces positive curvature are also enhanced. B. Lipid signaling. The enteroviruses and HCV stimulate phosphatidylinositol signaling. HCV and enteroviruses specifically recruit PI-4-kinases to phosphorylate PI to PI4P [–26**]. This can then be bound by viral or cellular PI4P-binding proteins to facilitate replication complex formation.

Figure 2. AMPK signaling and lipid metabolism

AMPK is a central regulator of cellular metabolism. Specific activators and inhibitors of AMPK and the downstream effectors that specifically modulate lipid metabolism are shown. In general, AMPK senses low energy conditions and once activated it inhibits lipid anabolic pathways to conserve energy, while stimulating lipid catabolism to generate. This is differentially manipulated in a number of viral infections. During HCV infection, AMPK activation in inhibited via activation of Akt/PKB [61*]. HCMV is also thought to activate Akt, however, recently it has been shown that AMPK is activated by HCMV via cAMKK [66,67]. HIV Tat may inhibit AMPK through Sirtuin 1(SIRT1) inhibition [60,62]. SV40 inhibits protein phosphatase 2 A (PP2A) leading to AMPK activation [63]. Vaccinia and Avian reovirus also activate AMPK through unknown mechanisms [–65].