Multifaceted roles for lipids in viral infection

Abstract

Viruses have evolved complex and dynamic interactions with their host cell. In recent years we have gained insight into the expanding roles for host lipids in the virus life cycle. In particular, viruses target lipid signaling, synthesis, and metabolism to remodel their host cells into an optimal environment for their replication. This review highlights examples from different viruses that illustrate the importance of these diverse virus-lipid interactions.

Figure 1

Roles for lipids in virus entry. (a) Lipids as direct viral receptors. The virus protein coat of non-enveloped viruses, such as polyomaviruses, can associate with lipids on the cell surface . In many cases these lipids display a carbohydrate moiety (brown) that directly interacts with the virus protein coat (yellow). This interaction leads to internalization of the virus and the initiation of infection. (b) Lipid receptors as indirect viral receptors. Viruses (yellow) such as HCV and BVDV, which associate with LDL in the blood, can be brought into proximity of a target cells via the association between LDL and its receptor (LDL-R) , . Subsequently, interaction with high-affinity cell-surface viral receptors (orange) facilitates infection. (c) Lipids as entry cofactors. Lipids can modulate the ability of a virus to enter the cell after initial receptor interactions. Many viruses (yellow) such as influenza, HIV, and Ebola virus enter cells at lipid microdomains (orange) or require lipid microdomains for some step of virus entry (reviewed in [86]). (d) Lipids as virus fusion cofactors. Some viruses (yellow), such as DENV, utilize specific lipids (green) in order to stimulate virus envelope fusion with target membranes .

Figure 2

Roles for lipids and lipid signaling in replication complex formation and function. (a) Phosphoinositide signaling. Phosphoinositides (PIs) are negatively charged lipids with a specific head-group that can be phosphorylated at different positions to generate PI-phosphates (PIPs). PIPs can direct cell signaling in a pro-viral manner or directly bind to virus proteins during HCV and enterovirus infection , . (b) Membrane curvature. There are several ways in which viruses can induce membrane curvature. First, the virus can cause the accumulation of cone-shaped lipids (such as lysophosphatidylcholine, LPC) in one leaflet of the membrane bilayer, and this can lead to membrane bending (top). Second, the virus can encode a membrane-associated protein that induces membrane curvature (e.g. HCV NS4B and flavivirus NS4A, middle) , . Third, the virus can utilize host membrane proteins that induce membrane curvature, such as reticulons (RTNs, bottom) , which have been shown to be required for BMV membrane rearrangements. It is important to note that these are not mutually exclusive and a virus could use several strategies to accomplish membrane bending. (c) Membrane expansion. WNV and DENV actively recruit lipid-biosynthesis machinery to generate lipids at sites of replication , . This helps to form the replication complexes. Further, membrane expansion might be important in generating lipids for the virus envelope. (d) Membrane dynamics. Viruses such as DENV or WNV, which recruit lipid-biosynthesis machinery to RCs, can modulate membrane fluidity and plasticity of replication complex membranes by desaturating lipid tails or leading to the accumulation of cholesterol, as has been seen during BMV infection , . These modulations probably lead to a membrane environment that is conducive to viral replication complex formation or function.

Figure 3

Modulating lipid metabolism can lead to the generation of energy for virus replication. The virus replication cycle is an energy-intensive process. Several reports have shown that the metabolic state of the infected cell can be shifted towards energy generation. Lipids and lipid stores represent vast pools of energy that are exploited during virus replication. Some viruses, such as HCV, appear to induce lipid metabolism both transcriptionally and post-transcriptionally to facilitate lipid oxidation and ATP generation. In addition, some viruses, such as DENV, can induce cytosolic processes, such as autophagy, which can lead to the degradation of lipid droplets (LDs) . The lipids released from LDs are oxidized at mitochondria, leading to oxidative phosphorylation of ADP to generate ATP.

Figure 4

Lipids, lipid signaling and membrane scission in virus assembly and release. (a) Lipids in HIV assembly and release. HIV assembly and release requires specific lipids at multiple stages. Initially, the structural protein Gag is recruited to pre-budding sites by its association with the lipid phosphatidylinositol-(4,5)-bisphosphate (PIP₂) . In addition, the membrane composition of these sites is specific, containing high amounts of sphingolipids and cholesterol . As the virus begins to bud, there is significant membrane curvature that needs to be induced and then resolved, a process known as membrane scission. In the case of HIV, membrane scission is accomplished by coopting cellular machinery known as the ESCRT machinery. The ESCRT complex facilitates membrane scission and the release of the virus . (b) Lipids in influenza virus assembly and release. Influenza A similarly associates with specific lipid microdomains during the budding process, however, the mechanism of membrane scission is significantly different. Instead of utilizing the ESCRT complex, the virus genome encodes the M2 protein, which serves an analogous function to the ESCRT complex and facilitates virus budding without a requirement for host machinery .