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Review
. 2019 Aug 8;11(8):733.
doi: 10.3390/v11080733.

Virophages of Giant Viruses: An Update at Eleven

Said Mougari  1   2 , Dehia Sahmi-Bounsiar  1   2 , Anthony Levasseur  1   2 , Philippe Colson  3   4 , Bernard La Scola  5   6
Affiliations
Review

Virophages of Giant Viruses: An Update at Eleven

Said Mougari et al. Viruses. .

Abstract

The last decade has been marked by two eminent discoveries that have changed our perception of the virology field: The discovery of giant viruses and a distinct new class of viral agents that parasitize their viral factories, the virophages. Coculture and metagenomics have actively contributed to the expansion of the virophage family by isolating dozens of new members. This increase in the body of data on virophage not only revealed the diversity of the virophage group, but also the relevant ecological impact of these small viruses and their potential role in the dynamics of the microbial network. In addition, the isolation of virophages has led us to discover previously unknown features displayed by their host viruses and cells. In this review, we present an update of all the knowledge on the isolation, biology, genomics, and morphological features of the virophages, a decade after the discovery of their first member, the Sputnik virophage. We discuss their parasitic lifestyle as bona fide viruses of the giant virus factories, genetic parasites of their genomes, and then their role as a key component or target for some host defense mechanisms during the tripartite virophage-giant virus-host cell interaction. We also present the latest advances regarding their origin, classification, and definition that have been widely discussed.

Keywords: coculture; giant virus; host-defense systems; metagenomic; satellite virus; virophage.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Timeline showing the chronological order of description of virophages isolated by co-culture and the major discoveries in the virophage field. RNV: Rio Negro Virophage. OLV: Organic Lake Virophage.
Figure 2
Figure 2
Phylogenetic reconstructions based on the capsid proteins of known virophages with their current/proposed taxonomy. The analysis was performed using MEGA version 7.0, applying the maximum-likelihood method and WAG ((Whelan & Goldman) model of evolution with 500 bootstrap replicates. Cutoff ≥ 50%, branches with 45%–50% support are marked with a red asterisk. UC: Under characterization.
Figure 3
Figure 3
Electronic microscopy observation of virophage particles and their replication cycle. (A) Negative staining electronic microscopy observation. (B–L) Transmission electronic microscopy images. (A) Morphology of purified Sputnik virophage particles (scale bar, 500 nm). (B,C) Sputnik and Guarani virions attached to the Mimivirus fibrils, respectively. (Scale bar, 500 nm and 200 nm). (D) Sputnik virophage invading the virus factory of acanthamoeba polyphaga Mimivirus (APMV) (scale bar, 1 µm). (E) Immature Sputnik virions observed in the cytoplasm of A. castellanii during co-infection with APMV (arrows) (scale bar, 200 nm). (F) Mature Sputnik virions (scale bar, 100 nm). (G–I) Virophages virions are commonly observed clustered inside typical cytoplasmic vesicles at the end of their replication cycles (arrows). (G) Sputnik progeny. (H) Zamilon progeny. (I) Guarani progeny (scale bars, 500 nm). (J,K) The genesis of abnormal Mimivirus particles has been observed during infection with virophages (arrows). (scale bars, 2 µm and 200 nm). (L) Encapsidation of virophage virions within the Mimivirus capsid (arrows) (scale bar, 200 nm). VF: Virus factory.
Figure 4
Figure 4
The parasitic lifestyle of virophages. (A) When the host cell is only infected by a giant virus, the latter establishes a cytoplasmic virus factory to replicate and generates new virions, and the host cell is most likely lysed at the end of its replication cycle. (B) When the host cell is co-infected with a giant virus and its virophage, the latter parasitizes the giant virus factory. The presence of virophages could seriously impact the infectivity of the giant virus by decreasing its replication efficiency and increasing the survival of the host cell. (C) When the giant virus genome is parasitized by a provirophage, the latter is expressed during the giant virus replication. The virophage is produced from the giant virus factory and inhibits the giant virus replication, thus increasing the host cell survival. VF: Virus factory.
Figure 5
Figure 5
Analogies between the CRISPR-Cas-, the Mavirus- immunity, and the MIMIVIRE-mediated immunity systems. All these mechanisms seem to implicate a record of genetic sequences and their integration into the genome of immunized organisms at their first step (adaptation). (A) For the CRISPR-Cas system, the host cell incorporates DNA pieces from the invading phage (proto-spacers) into the CRISPR arrays (spacers) (not represented here). This mechanism is mediated by the Cas machinery (in purple). (B) After an independent entry of Mavirus in the host cell, the virophage integrates its genome into the host genome and becomes latent. This mechanism seems to involve Mavirus-encoded retroviral integrase. (C) Mimiviruses from lineage A have integrated DNA sequences from Zamilon into their R349 genes. However, unlike the CRISPR-Cas and Mavirus systems, the integration mechanism of Zamilon DNA has not been characterized. The next step of the resistance mechanism is marked by the expression of the integrated genetic pieces. (A) For the CRISPR-Cas system, transcripts of the spacers are used as a guide for the Cas proteins to cut foreign DNA after new encounters with the phage. This phenomenon allows the host cell to survive and prevents the spread of the phage. (B) Infection of the host cell with Cafeteria roenbergensis virus (CroV) activates the expression and production of Mavirus. The host cell is lysed at the end of the CroV replication cycle but spread of the virophage progeny confers resistance to neighboring cells, allowing their survival and avoiding CroV spread. (C) The expression of the R349 gene containing Zamilon DNA and of the Cas-like proteins (in blue) is associated with the inhibition of Zamilon replication, conferring to lineage A mimiviruses a resistance to this virophage.
Figure 6
Figure 6
The parasites of the giants are giants. Plot comparing the virion and genome sizes for known virophages and some traditional satellite viruses. The ball sizes are proportional to the capsid sizes.
Figure 7
Figure 7
Virophages and satellite virus’ lifestyle. (A) The replication of virophages is supposed to occur entirely in the virus factory of its giant virus host, depending of the giant virus expression/replication complex. (B) The concept of satellite virus implicates that the virus initiates the expression and replication of its genome in the nucleus using the host cell machinery and then goes to the cytoplasm. In the cytoplasm, the satellite virus hijacks the morphogenesis machinery of its helper virus to produce its progeny.
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