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Viruses Jan 2023After the onset of the AIDS pandemic, HIV-1 (genus ) became the predominant model for studying retrovirus Env glycoproteins and their role in entry. However, HIV Env is... (Review)
Review
After the onset of the AIDS pandemic, HIV-1 (genus ) became the predominant model for studying retrovirus Env glycoproteins and their role in entry. However, HIV Env is an inadequate model for understanding entry of viruses in the , and genera. For example, oncogenic model system viruses such as Rous sarcoma virus (RSV, ), murine leukemia virus (MLV, ) and human T-cell leukemia viruses (HTLV-I and HTLV-II, ) encode Envs that are structurally and functionally distinct from HIV Env. We refer to these as Gamma-type Envs. Gamma-type Envs are probably the most widespread retroviral Envs in nature. They are found in exogenous and endogenous retroviruses representing a broad spectrum of vertebrate hosts including amphibians, birds, reptiles, mammals and fish. In endogenous form, gamma-type Envs have been evolutionarily coopted numerous times, most notably as placental syncytins (e.g., human SYNC1 and SYNC2). Remarkably, gamma-type Envs are also found outside of the . Gp2 proteins of filoviruses (e.g., Ebolavirus) and snake arenaviruses in the genus are gamma-type Env homologs, products of ancient recombination events involving viruses of different Baltimore classes. Distinctive hallmarks of gamma-type Envs include a labile disulfide bond linking the surface and transmembrane subunits, a multi-stage attachment and fusion mechanism, a highly conserved (but poorly understood) "immunosuppressive domain", and activation by the viral protease during virion maturation. Here, we synthesize work from diverse retrovirus model systems to illustrate these distinctive properties and to highlight avenues for further exploration of gamma-type Env structure and function.
Topics: Female; Pregnancy; Animals; Humans; Mice; Placenta; Gammaretrovirus; Alpharetrovirus; Leukemia Virus, Murine; Ebolavirus; Endogenous Retroviruses; HIV Seropositivity; Glycoproteins; Mammals
PubMed: 36851488
DOI: 10.3390/v15020274 -
International Journal of Radiation... Oct 2020
Topics: Acquired Immunodeficiency Syndrome; Alphapapillomavirus; Animals; Birds; COVID-19; Female; HIV; HIV Infections; Herpesvirus 4, Human; Human T-lymphotropic virus 1; Humans; Liver Cirrhosis; Lymphoma, AIDS-Related; Lymphoma, T-Cell; Nasopharyngeal Neoplasms; Oropharyngeal Neoplasms; Rous sarcoma virus; SARS-CoV-2; Sarcoma, Avian; Sarcoma, Kaposi; Uterine Cervical Neoplasms; Virus Diseases
PubMed: 32890509
DOI: 10.1016/j.ijrobp.2020.07.001 -
Viruses Sep 2021The small cellular molecule inositol hexakisphosphate (IP6) has been known for ~20 years to promote the in vitro assembly of HIV-1 into immature virus-like particles.... (Review)
Review
The small cellular molecule inositol hexakisphosphate (IP6) has been known for ~20 years to promote the in vitro assembly of HIV-1 into immature virus-like particles. However, the molecular details underlying this effect have been determined only recently, with the identification of the IP6 binding site in the immature Gag lattice. IP6 also promotes formation of the mature capsid protein (CA) lattice via a second IP6 binding site, and enhances core stability, creating a favorable environment for reverse transcription. IP6 also enhances assembly of other retroviruses, from both the Lentivirus and the Alpharetrovirus genera. These findings suggest that IP6 may have a conserved function throughout the family Retroviridae. Here, we discuss the different steps in the viral life cycle that are influenced by IP6, and describe in detail how IP6 interacts with the immature and mature lattices of different retroviruses.
Topics: Binding Sites; Capsid Proteins; HIV-1; Human Immunodeficiency Virus Proteins; Mutation; Phytic Acid; Retroviridae; Retroviridae Proteins; Reverse Transcription; Rous sarcoma virus; Virus Assembly; Virus Replication; gag Gene Products, Human Immunodeficiency Virus
PubMed: 34578434
DOI: 10.3390/v13091853 -
3'UTR of ALV-J can affect viral replication through promoting transcription and mRNA nuclear export.Journal of Virology Nov 20233'UTRs can affect gene transcription and post-transcriptional regulation in multiple ways, further influencing the function of proteins in a unique manner. Recently,...
3'UTRs can affect gene transcription and post-transcriptional regulation in multiple ways, further influencing the function of proteins in a unique manner. Recently, ALV-J has been mutating and evolving rapidly, especially the 3'UTR of viral genome. Meanwhile, clinical symptoms caused by ALV-J have changed significantly. In this study, we found that the ALV-J strains containing △-r-TM-type 3'UTR are the most abundant. By constructing ALV-J infectious clones and subgenomic vectors containing different 3'UTRs, we prove that 3'UTRs directly affect viral tissue preference and can promote virus replication as an enhancer. ALV-J strain containing 3'UTR of △-r-TM proliferated fastest in primary cells. All five forms of 3'UTRs can assist intron-containing viral mRNA nuclear export, with similar efficiency. ALV-J mRNA half-life is not influenced by different 3'UTRs. Our results dissect the roles of 3'UTR on regulating viral replication and pathogenicity, providing novel insights into potential anti-viral strategies.
Topics: 3' Untranslated Regions; Active Transport, Cell Nucleus; Gene Expression; Gene Expression Regulation; Virus Replication; Avian Leukosis Virus
PubMed: 37902396
DOI: 10.1128/jvi.01152-23 -
Microorganisms Dec 2023The Genus contains viruses pathogenic mainly for chickens, forming the Avian Sarcoma and Leukosis Virus group (ASLV). Cells of most Galliform species, besides chickens,...
The Genus contains viruses pathogenic mainly for chickens, forming the Avian Sarcoma and Leukosis Virus group (ASLV). Cells of most Galliform species, besides chickens, contain genetic elements (endogenous retroviruses, ERVs) that could recombine with other alpharetroviruses or express proteins, complementing defective ASLV, which may successfully replicate and cause disease. However, they are quite unknown, and only ALV-F, from ring-necked pheasants, has been partially published. Upon scrutiny of 53 genomes of different avian species, we found -like sequences only in 12 different Galliformes, including six full-length (7.4-7.6 Kbp) and 27 partial sequences. Phylogenetic studies of the regions studied (LTR, , , and ) consistently resulted in five almost identical clades containing the same ERVs: Clade I (presently known ASLVs); Clade II ( spp. ERVs); Clade IIIa ( ERVs); Clade IIIb ( spp. ERVs); and Clade IV ( spp. ERVs). The low identity scores suggested that each of these Clades may be considered a different species. ORF analysis revealed that putatively encoded proteins would be very similar in length and domains to those of other alpharetroviruses and thus potentially functional. This will undoubtedly contribute to better understanding the biology of defective viruses, especially in wild Galliformes, their evolution, and the danger they may represent for other wild species and the poultry industry.
PubMed: 38257913
DOI: 10.3390/microorganisms12010086 -
Glia Sep 2021Gliomas are the most common primary intrinsic brain tumors occurring in adults. Of all malignant gliomas, glioblastoma (GBM) is considered the deadliest tumor type due... (Review)
Review
Gliomas are the most common primary intrinsic brain tumors occurring in adults. Of all malignant gliomas, glioblastoma (GBM) is considered the deadliest tumor type due to diffuse brain invasion, immune evasion, cellular, and molecular heterogeneity, and resistance to treatments resulting in high rates of recurrence. An extensive understanding of the genomic and microenvironmental landscape of gliomas gathered over the past decade has renewed interest in pursuing novel therapeutics, including immune checkpoint inhibitors, glioma-associated macrophage/microglia (GAMs) modulators, and others. In light of this, predictive animal models that closely recreate the conditions and findings found in human gliomas will serve an increasingly important role in identifying new, effective therapeutic strategies. Although numerous syngeneic, xenograft, and transgenic rodent models have been developed, few include the full complement of pathobiological features found in human tumors, and therefore few accurately predict bench-to-bedside success. This review provides an update on how genetically engineered rodent models based on the replication-competent avian-like sarcoma (RCAS) virus/tumor virus receptor-A (tv-a) system have been used to recapitulate key elements of human gliomas in an immunologically intact host microenvironment and highlights new approaches using this model system as a predictive tool for advancing translational glioma research.
Topics: Animals; Avian Sarcoma Viruses; Brain Neoplasms; Disease Models, Animal; Glioma; Humans; Oncogenic Viruses; Receptors, Virus; Sarcoma; Tumor Microenvironment
PubMed: 33638562
DOI: 10.1002/glia.23984 -
Molecular Therapy. Nucleic Acids Mar 2022DNA-modifying technologies, such as the CRISPR-Cas9 system, are promising tools in the field of gene and cell therapies. However, high and prolonged expression of...
DNA-modifying technologies, such as the CRISPR-Cas9 system, are promising tools in the field of gene and cell therapies. However, high and prolonged expression of DNA-modifying enzymes may cause cytotoxic and genotoxic side effects and is therefore unwanted in therapeutic approaches. Consequently, development of new and potent short-term delivery methods is of utmost importance. Recently, we developed non-integrating gammaretrovirus- and MS2 bacteriophage-based Gag.MS2 (g.Gag.MS2) particles for transient transfer of non-retroviral CRISPR-Cas9 RNA into target cells. In the present study, we further improved the technique by transferring the system to the alpharetroviral vector platform (a.Gag.MS2), which significantly increased CRISPR-Cas9 delivery into target cells and allowed efficient targeted knockout of endogenous genes in primary murine fibroblasts as well as primary human fibroblasts, hepatocytes, and cord-blood-derived CD34 stem and progenitor cells. Strikingly, co-packaging of mRNA and multiple single guide RNAs (sgRNAs) into a.Gag.MS2 chimera displayed efficient targeted knockout of up to three genes. Co-transfection of single-stranded DNA donor oligonucleotides during CRISPR-Cas9 particle production generated all-in-one particles, which mediated up to 12.5% of homology-directed repair in primary cell cultures. In summary, optimized a.Gag.MS2 particles represent a versatile tool for short-term delivery of DNA-modifying enzymes into a variety of target cells, including primary murine and human cells.
PubMed: 35141043
DOI: 10.1016/j.omtn.2021.12.033 -
Journal of Virology Sep 2022The receptor of the subgroup A avian leukosis virus (ALV-A) in chicken is Tva, which is the homologous protein of human CD320 (huCD320), contains a low-density...
The receptor of the subgroup A avian leukosis virus (ALV-A) in chicken is Tva, which is the homologous protein of human CD320 (huCD320), contains a low-density lipoprotein (LDL-A) module and is involved in the uptake of transcobalamin bound vitamin B/cobalamin (Cbl). To map the functional determinants of Tva responsible for ALV-A receptor activity, a series of chimeric receptors were created by swapping the LDL-A module fragments between huCD320 and Tva. These chimeric receptors were then used for virus entry and binding assays to map the minimal ALV-A functional domain of Tva. The results showed that Tva residues 49 to 71 constituted the minimal functional domain that directly interacted with the ALV-A gp85 protein to mediate ALV-A entry. Single-residue substitution analysis revealed that L55 and W69, which were spatially adjacent on the surface of the Tva structure, were key residues that mediate ALV-A entry. Structural alignment results indicated that L55 and W69 substitutions did not affect the Tva protein structure but abolished the interaction force between Tva and gp85. Furthermore, substituting the corresponding residues of huCD320 with L55 and W69 of Tva converted huCD320 into a functional receptor of ALV-A. Importantly, soluble huCD320 harboring Tva L55 and W69 blocked ALV-A entry. Finally, we constructed a gene-edited cell line with L55R and W69L substitutions that could fully resist ALV-A entry, while Cbl uptake was not affected. Collectively, our findings suggested that amino acids L55 and W69 of Tva were key for mediating virus entry. Retroviruses bind to cellular receptors through their envelope proteins, which is a crucial step in infection. While most retroviruses require two receptors for entry, ALV-A requires only one. Various alleles conferring resistance to ALV-A, including (C40W substitution), (frame-shifting four-nucleotide insertion), , , , and (deletion in the first intron), are known. However, the detailed entry mechanism of ALV-A in chickens remains to be explored. We demonstrated that Tva residues L55 and W69 were key for ALV-A entry and were important for correct interaction with ALV-A gp85. Soluble Tva and huCD320 harboring the Tva residues L55 and W69 effectively blocked ALV-A infection. Additionally, we constructed gene-edited cell lines targeting these two amino acids, which completely restricted ALV-A entry without affecting Cbl uptake. These findings contribute to a better understanding of the infection mechanism of ALV-A and provided novel insights into the prevention and control of ALV-A.
Topics: Amino Acids; Animals; Avian Leukosis; Avian Leukosis Virus; Avian Proteins; Chickens; Humans; Lipoproteins, LDL; Nucleotides; Receptors, Virus; Transcobalamins; Vitamin B 12
PubMed: 36069550
DOI: 10.1128/jvi.00678-22 -
Frontiers in Immunology 2022Avian leukosis virus (ALV) causes various diseases associated with tumor formation and decreased fertility. Moreover, ALV induces severe immunosuppression, increasing... (Review)
Review
Avian leukosis virus (ALV) causes various diseases associated with tumor formation and decreased fertility. Moreover, ALV induces severe immunosuppression, increasing susceptibility to other microbial infections and the risk of failure in subsequent vaccination against other diseases. There is growing evidence showing the interaction between ALV and the host. In this review, we will survey the present knowledge of the involvement of host factors in the important molecular events during ALV infection and discuss the futuristic perspectives from this angle.
Topics: Animals; Avian Leukosis; Avian Leukosis Virus; Chickens; Virus Replication
PubMed: 35693802
DOI: 10.3389/fimmu.2022.907287 -
Journal of Virology Nov 2023The synergy of two oncogenic retroviruses is an essential phenomenon in nature. The synergistic replication of ALV-J and REV in poultry flocks increases...
The synergy of two oncogenic retroviruses is an essential phenomenon in nature. The synergistic replication of ALV-J and REV in poultry flocks increases immunosuppression and pathogenicity, extends the tumor spectrum, and accelerates viral evolution, causing substantial economic losses to the poultry industry. However, the mechanism of synergistic replication between ALV-J and REV is still incompletely elusive. We observed that microRNA-155 targets a dual pathway, PRKCI-MAPK8 and TIMP3-MMP2, interacting with the U3 region of ALV-J and REV, enabling synergistic replication. This work gives us new targets to modulate ALV-J and REV's synergistic replication, guiding future research on the mechanism.
Topics: Animals; Reticuloendotheliosis virus; Avian Leukosis; Avian Leukosis Virus; Chickens; Poultry Diseases; MicroRNAs; Virus Replication
PubMed: 37909729
DOI: 10.1128/jvi.00937-23