
Grey wolves in the Northwest Territories of Canada harbor a high prevalence and diversity of fox circovirus, a lineage of canine circovirus, suggesting they are reservoir hosts for these viruses.


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Canine circoviruses (CanineCV) have a worldwide distribution in dogs and are occasionally detected in wild carnivorans, indicating their ability for cross-species transmission. However, fox circovirus, a lineage of CanineCV, has been identified exclusively in wild canids. We analyzed spleen samples from 159 grey wolves from the Northwest Territories, Canada, to investigate the molecular epidemiology of CanineCV and formulate hypotheses about virus ecology and evolution. Overall, 72 out of 159 (45.3%) animals tested positive. Virus prevalence was similar between males and females, adults and juveniles, and across the investigated years and locations. CanineCV infection was not associated with a poor body condition. While the percentage of co-infections with canine parvoviruses, investigated in a previous study, was high (63/72, 87.5%), the rate of parvovirus infection in CanineCV-negative animals was significantly lower (42/87, 48.3%, χ2 = 27.03, p < 0.001), and CanineCV infection was associated with a 7.5- and 2.4-fold increase in the risk of acquiring canine parvovirus 2 or canine bufavirus infections, respectively (odds ratios: 3.5-16.9 and 1.3-5.8). Although common risk factors cannot be ruled out, this suggests that CanineCV may facilitate parvoviral super-infections. Sequencing revealed high CanineCV genetic diversity, further exacerbated by recombination. Of the 69 sequenced strains, 87.5% were fox circoviruses, five were related to a fox circovirus-like recombinant strain, and one belonged to a distant lineage. In the phylogenetic analysis, the virus sequences were distributed according to sampling locations, with some viruses being geographically restricted. Different clades of viruses were identified in the same areas and over multiple years (2007-2019), indicating the co-existence of multiple endemic lineages in the investigated area. Phylogenetic analysis of all available complete fox circovirus genomes (32 from foxes and 15 from wolves from North America and Europe) demonstrated four lineages, each including sequences from this study. Within each lineage, strains segregated geographically and not by host. This implies that, although multiple lineages co-exist, viruses do not frequently move between locations. Finally, viruses from Europe and North America were mixed, indicating that the origin of the four lineages might predate the segregation of European and American wolf and fox populations. Given the high prevalence and diversity of fox circoviruses in wolves, these animals should be considered reservoir hosts for these viruses. Although we cannot exclude a lower susceptibility of dogs, the lack of fox circovirus in dogs could be due to environmental circumstances that prevented its spread to dogs. Given the high diversity and wild host specificity, we presume a long-lasting association between fox circovirus and canine hosts and hypothesize a higher likelihood of transmission from dogs to wild animals than vice versa. Further studies should investigate other sympatric wild species and additional locations to explore the possible existence of additional maintenance hosts and the reasons behind the marked difference in cross-species transmission dynamics among CanineCV lineages.

### Competing Interest Statement

The authors have declared no competing interest.

Diverse fox circovirus (Circovirus canine) variants circulate at high prevalence in grey wolves (Canis lupus) from the Northwest Territories, Canada

diverse-fox-circovirus-circovirus-canine-variants-circulate-at-high-prevalence-in-grey-wolves-canis-lupus-in-the-northwest-territories-of-canada


Diverse fox circovirus (Circovirus canine) variants circulate at high prevalence in grey wolves (Canis lupus) in the Northwest Territories of Canada


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HCMV pUL71 protein contains a viral MIM2-like motif (vMIM2) that binds the VPS4A MIT domain, recruiting VPS4A to the cytoplasmic viral assembly compartment (cVAC) during HCMV infection.


The AAA-type ATPase VPS4 is recruited by proteins of the endosomal sorting complex required for transport III (ESCRT-III) to catalyse membrane constriction and membrane fission. VPS4A accumulates at the cytoplasmic viral assembly complex (cVAC) of cells infected with human cytomegalovirus (HCMV), the site where nascent virus particles obtain their membrane envelope. Here we show that VPS4A is recruited to the cVAC via interaction with pUL71. Sequence analysis, deep-learning structure prediction, molecular dynamics and mutagenic analysis identify a short peptide motif in the C-terminal region of pUL71 that is necessary and sufficient for the interaction with VPS4A. This motif is predicted to bind the same groove of the N-terminal VPS4A Microtubule-Interacting and Trafficking (MIT) domain as the Type 2 MIT-Interacting Motif (MIM2) of cellular ESCRT-III components, and this viral MIM2-like motif (vMIM2) is conserved across β-herpesvirus pUL71 homologues. However, recruitment of VPS4A by pUL71 is dispensable for HCMV morphogenesis or replication and the function of the conserved vMIM2 during infection remains enigmatic. VPS4-recruitment via a vMIM2 represents a previously unknown mechanism of molecular mimicry in viruses, extending previous observations that herpesviruses encode proteins with structural and functional homology to cellular ESCRT-III components.

### Competing Interest Statement

The authors have declared no competing interest.

Human cytomegalovirus deploys molecular mimicry to recruit VPS4A to sites of virus assembly

hcmv-exploits-molecular-mimicry-to-recruit-vps4a-for-virus-assembly


HCMV Exploits Molecular Mimicry to Recruit VPS4A for Virus Assembly



Glycosylation at N343 affects SARS-CoV-2 RBD structure and co-receptor binding across variants.


Glycosylation of the SARS-CoV-2 spike (S) protein represents a key target for viral evolution because it affects both viral evasion and fitness. Successful variations in the glycan shield are difficult to achieve though, as protein glycosylation is also critical to folding and to structural stability. Within this framework, the identification of glycosylation sites that are structurally dispensable can provide insight into the evolutionary mechanisms of the shield and inform immune surveillance. In this work we show through over 45 μs of cumulative sampling from conventional and enhanced molecular dynamics (MD) simulations, how the structure of the immunodominant S receptor binding domain (RBD) is regulated by N -glycosylation at N343 and how this glycan’s structural role changes from WHu-1, alpha (B.1.1.7), and beta (B.1.351), to the delta (B.1.617.2) and omicron (BA.1 and BA.2.86) variants. More specifically, we find that the amphipathic nature of the N -glycan is instrumental to preserve the structural integrity of the RBD hydrophobic core and that loss of glycosylation at N343 triggers a specific and consistent conformational change. We show how this change allosterically regulates the conformation of the receptor binding motif (RBM) in the WHu-1, alpha and beta RBDs, but not in the delta and omicron variants, due to mutations that reinforce the RBD architecture. In support of these findings, we show that the binding of the RBD to monosialylated ganglioside co-receptors is highly dependent on N343 glycosylation in the WHu-1, but not in the delta RBD, and that affinity changes significantly across VoCs. Ultimately, the molecular and functional insight we provide in this work reinforces our understanding of the role of glycosylation in protein structure and function and it also allows us to identify the structural constraints within which the glycosylation site at N343 can become a hotspot for mutations in the SARS-CoV-2 S glycan shield.

### Competing Interest Statement

The authors have declared no competing interest.

#GotGlycans: Role of N343 Glycosylation on the SARS-CoV-2 S RBD Structure and Co-Receptor Binding Across Variants of Concern

role-of-n343-glycosylation-on-sars-cov-2-rbd-structure-and-co-receptor-binding


Role of N343 Glycosylation on SARS-CoV-2 RBD Structure and Co-Receptor Binding



The author demonstrates that TRMT1 is cleaved by the SARS-CoV-2 main protease, impacting tRNA modification levels and viral replication efficiency.


Nonstructural protein 5 (Nsp5) is the main protease of SARS-CoV-2 that cleaves viral polyproteins into individual polypeptides necessary for viral replication. Here, we show that Nsp5 binds and cleaves human tRNA methyltransferase 1 (TRMT1), a host enzyme required for a prevalent post-transcriptional modification in tRNAs. Human cells infected with SARS-CoV-2 exhibit a decrease in TRMT1 protein levels and TRMT1-catalyzed tRNA modifications, consistent with TRMT1 cleavage and inactivation by Nsp5. Nsp5 cleaves TRMT1 at a specific position that matches the consensus sequence of SARS-CoV-2 polyprotein cleavage sites, and a single mutation within the sequence inhibits Nsp5-dependent proteolysis of TRMT1. The TRMT1 cleavage fragments exhibit altered RNA binding activity and are unable to rescue tRNA modification in TRMT1-deficient human cells. Compared to wildtype human cells, TRMT1-deficient human cells infected with SARS-CoV-2 exhibit reduced levels of intracellular viral RNA. These findings provide evidence that Nsp5-dependent cleavage of TRMT1 and perturbation of tRNA modification patterns contribute to the cellular pathogenesis of SARS-CoV-2 infection.

### Competing Interest Statement

The authors have declared no competing interest.

Proteolytic cleavage and inactivation of the TRMT1 tRNA modification enzyme by SARS-CoV-2 main protease

proteolytic-cleavage-of-trmt1-by-sars-cov-2-main-protease


Proteolytic Cleavage of TRMT1 by SARS-CoV-2 Main Protease



The author explores the impact of host cell-dependent glycosylation differences on SIV infectivity and neutralization sensitivity, highlighting the importance of these factors in shaping viral characteristics.


The human immunodeficiency virus (HIV) envelope protein (Env) mediates viral entry into host cells and is the primary target for the humoral immune response. Env is extensively glycosylated, and these glycans shield underlying epitopes from neutralizing antibodies. The glycosylation of Env is influenced by the type of host cell in which the virus is produced. Thus, HIV is distinctly glycosylated by CD4+ T cells, the major target cells, and macrophages. However, the specific differences in glycosylation between viruses produced in these cell types have not been explored at the molecular level. Moreover, the impact of these differences on viral spread and neutralization sensitivity remains largely unknown. To address these questions, we employed the simian immunodeficiency virus (SIV) model. Glycan analysis revealed higher relative levels of oligomannose-type N -glycans in SIV from CD4+ T cells (T-SIV) compared to SIV from macrophages (M-SIV), and the complex-type N -glycans profiles differed between the two viruses. Notably, M-SIV demonstrated greater infectivity than T-SIV, even when accounting for Env incorporation, suggesting that host cell-dependent factors influence infectivity. Further, M-SIV was more efficiently disseminated by HIV binding cellular lectins. We also evaluated the influence of cell type-dependent differences on SIV’s vulnerability to carbohydrate binding agents (CBAs) and neutralizing antibodies. T-SIV demonstrated greater susceptibility to mannose-specific CBAs, possibly due to its elevated expression of oligomannose-type N -glycans. In contrast, M-SIV exhibited higher susceptibility to neutralizing sera in comparison to T-SIV. These findings underscore the importance of host cell-dependent attributes of SIV, such as glycosylation, in shaping both infectivity and the potential effectiveness of intervention strategies.

### Competing Interest Statement

The authors have declared no competing interest.

Macrophage- and CD4+ T cell-derived SIV differ in glycosylation, infectivity and neutralization sensitivity

comparing-siv-glycosylation-infectivity-and-neutralization-sensitivity


Comparing SIV Glycosylation, Infectivity, and Neutralization Sensitivity



The author explores the three-dimensional organization of viral genomes within a protein capsid, revealing insights into DNA packaging mechanisms and potential drug targets at the genome-capsid interface.


Multiresolution computational simulations generate all-atom models of a complete packaged virus particle.

The structure and physical properties of a packaged bacteriophage particle - Nature

unveiling-the-structure-of-a-packaged-bacteriophage-particle


Unveiling the Structure of a Packaged Bacteriophage Particle



The author argues that mammalian coronaviruses originated recently in bats and diversified through host switches, challenging previous notions of long-term codiversification with hosts.


Several coronaviruses infect humans, with three, including the SARS-CoV2, causing diseases. While coronaviruses are especially prone to induce pandemics, we know little about their evolutionary history, host-to-host transmissions, and biogeography, which impedes the prediction of future transmission scenarios. One of the difficulties lies in dating the origination of the family, a particularly challenging task for RNA viruses in general. Previous cophylogenetic tests of virus-host associations, including in the Coronaviridae family, have suggested a virus-host codiversification history stretching many millions of years. Here, we establish a framework for robustly testing scenarios of ancient origination and codiversification versus recent origination and diversification by host switches. Applied to coronaviruses and their mammalian hosts, our results support a scenario of recent origination of coronaviruses in bats and diversification by host switches, with preferential host switches within mammalian orders. Hotspots of coronavirus diversity, concentrated in East Asia and Europe, are consistent with this scenario of relatively recent origination and localized host switches. Spillovers from bats to other species are rare, but have the highest probability to be towards humans than to any other mammal species, implicating humans as the evolutionary intermediate host. The high host-switching rates within orders, as well as between humans, domesticated mammals, and non-flying wild mammals, indicates the potential for rapid additional spreading of coronaviruses across the world. Our results suggest that the evolutionary history of extant mammalian coronaviruses is recent, and that cases of long-term virus–host codiversification have been largely over-estimated.

### Competing Interest Statement

The authors have declared no competing interest.

Recent evolutionary origin and localized diversity hotspots of mammalian coronaviruses

Evolutionary-Origins-of-Mammalian-Coronaviruses-Revealed


Evolutionary Origins of Mammalian Coronaviruses Revealed
