Protoparvovirus Interactions with the Cellular DNA Damage Response

Chapparvoviruses (ChPVs) comprise a divergent, recently identified group of parvoviruses (family Parvoviridae), associated with nephropathy in immunocompromised laboratory mice and with prevalence in deep sequencing results of livestock showing diarrhea. Here, we investigate the biological and evolutionary characteristics of ChPVs via comparative in silico analyses, incorporating sequences derived from endogenous parvoviral elements (EPVs) as well as exogenous parvoviruses. We show that ChPVs are an ancient lineage within the Parvoviridae, clustering separately from members of both currently established subfamilies. Consistent with this, they exhibit a number of characteristic features, including several putative auxiliary protein-encoding genes, and capsid proteins with no sequence-level homology to those of other parvoviruses. Homology modeling indicates the absence of a β-A strand, normally part of the luminal side of the parvoviral capsid protein core. Our findings demonstrate that the ChPV lineage infects an exceptionally broad range of host species, including both vertebrates and invertebrates. Furthermore, we observe that ChPVs found in fish are more closely related to those from invertebrates than they are to those of amniote vertebrates. This suggests that transmission between distantly related host species may have occurred in the past and that the Parvoviridae family can no longer be divided based on host affiliation.

Section: Discussionmentioning

confidence: 99%

An Ancient Lineage of Highly Divergent Parvoviruses Infects both Vertebrate and Invertebrate Hosts

Pénzes

Souza

Agbandje‐McKenna

et al. 2019

“…Many cellular DDR proteins including DNA repair and DNA replication factors localize to VRCs where they are proposed to play roles in viral genome replication, the resolution of genome-replication intermediates, and the processing of viral genomes for packaging [8,10,11,14,18,69,[120][121][122][123]. Thus, DDR proteins may be considered common components of VRCs.…”

Section: The Composition Of Replication Compartmentsmentioning

confidence: 99%

Replication Compartments of DNA Viruses in the Nucleus: Location, Location, Location

Charman

Weitzman

2020

DNA viruses that replicate in the nucleus encompass a range of ubiquitous and clinically important viruses, from acute pathogens to persistent tumor viruses. These viruses must co-opt nuclear processes for the benefit of the virus, whilst evading host processes that would otherwise attenuate viral replication. Accordingly, DNA viruses induce the formation of membraneless assemblies termed viral replication compartments (VRCs). These compartments facilitate the spatial organization of viral processes and regulate virus-host interactions. Here, we review advances in our understanding of VRCs. We cover their initiation and formation, their function as the sites of viral processes, and aspects of their composition and organization. In doing so, we highlight ongoing and emerging areas of research highly pertinent to our understanding of nuclear-replicating DNA viruses.Viruses 2020, 12, 151 2 of 20 The Initiation and Formation of Replication CompartmentsDNA viruses that replicate in the nucleus exhibit a diverse array of strategies to complete their replication cycle and ultimately produce progeny virions. Despite their many differences, the strategies employed by DNA viruses to initiate productive infection and establish VRCs share many features in common. Indeed, it is likely that all DNA viruses that replicate in the nucleus form VRCs. Following penetration of the host cell and the transport of viral capsids/cores, viral DNA genomes enter the nucleus, where they begin a program of temporally regulated gene expression that initiates productive infection [1,2]. Early gene products include viral proteins required to manipulate the host-cell environment and replicate the viral genome. Viral replication proteins interact with the viral genome and initiate genome replication leading to VRC formation, which is often in concert with certain co-opted host proteins. However, these viruses must overcome several challenges to form VRCs successfully. Firstly, incoming genomes must avoid cellular intrinsic antiviral defenses and homeostatic regulatory pathways such as elements of the DNA damage response (DDR) that respond to the presence of foreign DNA and act to suppress viral gene expression [3][4][5][6][7][8][9][10]. Secondly, VRCs typically form at specific sites within the nucleus, suggesting that viral genomes need to be targeted to these sites in order to initiate VRC formation [6,11,12]. Furthermore, it has been hypothesized that the formation and growth of VRCs may require manipulation of the nuclear environment and the re-organization of host chromatin to overcome the spatial restraints of the nucleus [11][12][13][14][15]. In this section, we review key features of VRC initiation and highlight some major challenges to VRC formation. Interplay between Viral Replication Compartment Formation and Promyelocytic Leukemia Protein Nuclear BodiesA common theme amongst many nuclear-replicating DNA viruses is initiation of VRCs at sites in close proximity to promyelocytic leukemia protein (PML) nuclear bodies (NBs). Since the dis...

“…Various factors that are overexpressed in cancer cells are active in controlling PV nuclear transfer (e.g., CDK1/PKCα-mediated rupture of the nuclear envelope [47]), NS1 activities (e.g., PDK1/PKB/PKC involvement in the phosphorylation of NS1 [48]), viral gene expression (e.g., members of the E2F, Ets, and ATF families of transcription factors are needed to activate the P4 promoter [44,47,49]), virus replication (e.g., interaction with components of the DNA damage response, such as RPA-P32, γH2AX, NBS1-P, ATR, ATRIP, and ATM, which are recruited in the subnuclear PV replication centres, the so-called APAR bodies [50]), viral progeny capsid assembly and nuclear transport (e.g., MAP3K-mediated phosphorylation of capsid intermediates [51]), and virus egress (e.g., XPO1, PKB, PKCη, and Radexin, which regulate various steps involved in trafficking of the virus outside the cell [52,53,54]).…”

Section: H-1pv At the Preclinical Level: Acquiring License To Killmentioning

confidence: 99%

H-1 Parvovirus as a Cancer-Killing Agent: Past, Present, and Future

Bretscher

Marchini

2019

The rat protoparvovirus H-1PV is nonpathogenic in humans, replicates preferentially in cancer cells, and has natural oncolytic and oncosuppressive activities. The virus is able to kill cancer cells by activating several cell death pathways. H-1PV-mediated cancer cell death is often immunogenic and triggers anticancer immune responses. The safety and tolerability of H-1PV treatment has been demonstrated in early clinical studies in glioma and pancreatic carcinoma patients. Virus treatment was associated with surrogate signs of efficacy including immune conversion of tumor microenvironment, effective virus distribution into the tumor bed even after systemic administration, and improved patient overall survival compared with historical control. However, monotherapeutic use of the virus was unable to eradicate tumors. Thus, further studies are needed to improve H-1PV’s anticancer profile. In this review, we describe H-1PV’s anticancer properties and discuss recent efforts to improve the efficacy of H-1PV and, thereby, the clinical outcome of H-1PV-based therapies.