Lipid Tales of Viral Replication and Transmission

Abstract

Positive-strand RNA viruses are the largest group of RNA viruses on Earth and cellular membranes are critical for all aspects of their life cycle, from entry and replication to exit. In particular, membranes serve as platforms for replication and as carriers to transmit these viruses to other cells, the latter either as an envelope surrounding a single virus or as the vesicle containing a population of viruses. Notably, many animal and human viruses appear to induce and exploit phosphatidylinositol 4-phosphate/cholesterol-enriched membranes for replication, whereas many plant and insect-vectored animal viruses utilize phosphatidylethanolamine/cholesterol-enriched membranes for the same purpose; and phosphatidylserine-enriched membrane carriers are widely used by both single and populations of viruses for transmission. Here I discuss the implications for viral pathogenesis and therapeutic development of this remarkable convergence on specific membrane lipid blueprints for replication and transmission.

Keywords: RNA virus; autophagy; cholesterol; exosome; membrane; multivesicular body; phosphatidylethanolamine; phosphatidylinositol 4-phosphate; phosphatidylserine; population.

Figure 1. (+) ssRNA viruses exploit PE and PI4P lipid enriched organelles for replication

Many plant and insect vectored animal (+) ssRNA viruses utilize the surface of PE/cholesterol rich membranes for genome replication. Organelles with pre-existing pools of PE and cholesterol such as mitochondria and peroxisomes are hijacked and further enriched in these lipids. In contrast, many human and animal (+) ssRNA viruses appear to rely on PI4P and cholesterol enriched membranes for replication. Upon infection, these viruses hijack host Type III PI4 kinases and cholesterol trafficking pathways to transform the secretory pathway membranes (ER, Golgi, TGN) into replication organelles that are highly enriched in PI4P and cholesterol. The PE/cholesterol and PI4P/cholesterol enriched membranes facilitate viral RNA synthesis by helping dock and concentrate viral replication proteins; by stimulating viral enzymatic reactions; and by generating high curvature membrane pockets that can concentrate and segregate viral replication machinery from the host innate immune defenses.

Figure 2. RNA viruses exit cells in PS lipid enriched membranes as single or populations of viral particles

Both enveloped and non-enveloped viruses exploit PS-enriched membranes to be released from cells either as single particles (Dengue, West Nile, Ebola, VSV, HIV) or as populations (PV, CVB3, rhinovirus, HAV, HEV). PS lipids are obtained by budding into the ER; by budding off from the plasma membrane; or by being captured in secretory autophagosomes and multivesicular bodies (MVB) and subsequently released to the outside in extracellular vesicles. The PS-enriched membranes can potentially suppress a widespread, adaptive immune response against the virus. In addition, enhanced infection efficiency is observed by viruses traveling as populations within vesicles (e.g. PV, CVB3, rhinovirus [3]). This is potentially due to a vesicle being able to simultaneously deliver multiple viral genomes into the host cell, allowing subsequent cooperative interactions to take place among viral quasispecies that benefit replication.