Intercellular Transmission of Naked Viruses through Extracellular Vesicles: Focus on Polyomaviruses

Abstract

Extracellular vesicles have recently emerged as a novel mode of viral transmission exploited by naked viruses to exit host cells through a nonlytic pathway. Extracellular vesicles can allow multiple viral particles to collectively traffic in and out of cells, thus enhancing the viral fitness and diversifying the transmission routes while evading the immune system. This has been shown for several RNA viruses that belong to the Picornaviridae, Hepeviridae, Reoviridae, and Caliciviridae families; however, recent studies also demonstrated that the BK and JC viruses, two DNA viruses that belong to the Polyomaviridae family, use a similar strategy. In this review, we provide an update on recent advances in understanding the mechanisms used by naked viruses to hijack extracellular vesicles, and we discuss the implications for the biology of polyomaviruses.

Keywords: BKPyV; JCPyV; MCPyV; Polyomavirus; SV40; TSPyV; en bloc transmission; extracellular vesicles; neutralizing antibodies.

Figure 1

Origin of extracellular vesicles (EVs) and EV hijacking by naked viruses. EVs can directly bud at the plasma membrane as microvesicles (1). They can also bud into multivesicular bodies (MVBs) and form intraluminal vesicles (ILVs) that are released as exosomes as a result of the fusion of MVBs with the plasma membrane (2). EVs can also be released after the fusion of double-membraned autophagosomes with the plasma membrane, a mechanism termed secretory autophagy (3). Apoptosis can also generate EVs called apoptotic bodies, but this mechanism is not shown in the figure. Examples of naked viruses that exploit these different EV production pathways are mentioned in light blue.

Figure 2

Model of the BK and JC polyomavirus life cycle. (1) Infection begins with binding of naked virions (1a) or EV-associated virions (1b) to the cell surface. This is followed by endocytosis and transport to the endosomes (2a and 2b). EV membranes may be disrupted by endosomal lipases and lipid extractor proteins to release free virions in the endosomes. Then, viral particles traffic from the endosomes to the endoplasmic reticulum (ER) (3). In the ER, partial capsid uncoating occurs, which creates a hydrophobic surface exposing VP2/VP3 that integrates into the ER membrane and leads to the release of partially uncoated viruses into the cytosol (4). The viral genome is then transported into the nucleus via the nuclear pore complex thanks to VP2/VP3 nuclear localization signals and the importin α/β1 import pathway (5). Then, early genes are expressed (6), and early proteins are translocated into the nucleus to initiate viral DNA replication (7). Late genes are then expressed (8), and late proteins are translocated into the nucleus. After translocation, VP1, VP2, and VP3 self-assemble to form capsids into which newly synthetized double-stranded viral DNA is packaged (9). Progeny virions are released from infected cells as naked virions after cell lysis (10) or through a nonlytic pathway generating EV-associated virions (11). Free naked viral particles can also derive from EVs, as a result of spontaneous breakage (12). Adapted from [55].