Unique Tropism and Entry Mechanism of Mumps Virus.
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ABSTRACT:
SUBMITTER: Kubota M
PROVIDER: S-EPMC8471308 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AbstractBackgroundHIV-1 entry into cells is mediated by sequential binding of target cell CD4 and CCR5 or CXCR4 to the metastable envelope (Env) trimer of gp120-gp41 heterodimers (Figure 1). We determined that MF275, a single diastereomer of the small molecule entry inhibitor PF-68742, is necessary and sufficient to inhibit entry of a subset of HIV-1 strains. We investigated the mechanism of MF275.MethodsRecombinant luciferase-expressing HIV-1 pseudotyped by wild-type or mutant HIV-1 Envs was incubated with MF275, other entry inhibitors, and/or antibodies. The virus-inhibitor mixture was added to CD4+ CCR5+ or CD4? CCR5+ target cells and luciferase activity measured.ResultsUnlike other entry inhibitors, MF275 not only reversibly inhibited the infection of CD4+ CCR5+ cells by some HIV-1 strains, but also irreversibly enhanced the infection of CD4? CCR5+ cells by others. In both cases, the strain susceptibility profiles were unique from those of CD4-mimetics, BMS-378806, and maraviroc. Furthermore, MF275 activity was not affected by mutations conferring resistance to other entry inhibitors and vice versa. In line with its activating activity, MF275 sensitized susceptible Envs to neutralization by a variety of broadly neutralizing antibodies against different epitopes. Changes in the gp120 C5 and gp41 FP regions conferred resistance to MF275 inhibition but not activation. Furthermore, sensitivity to other entry inhibitors in the presence of MF275 indicated that inhibition and activation target different conformational intermediates along the entry pathway, with the former targeting the prehairpin intermediate.ConclusionMF275 is unique among HIV-1 entry inhibitors. Depending on the conformation of the target Env, which appears related to the gp120-gp41 interface, MF275 mediates inhibition or activation via distinct mechanisms (Figure 2). Further characterization of the MF275 mechanisms and binding site/s will advance understanding of the HIV-1 entry pathway as well as assist optimization of its clinical utility as an antiretroviral in multi-class drug resistance and potentially as an adjunct to vaccines. Disclosures All authors: No reported disclosures.
| S-EPMC6255539 | biostudies-other
Project description:Mumps virus (MuV) is an important aerosol-transmitted human pathogen causing epidemic parotitis, meningitis, encephalitis, and deafness. MuV preferentially uses a trisaccharide containing ?2,3-linked sialic acid as a receptor. However, given the MuV tropism toward glandular tissues and the central nervous system, an additional glycan motif(s) may also serve as a receptor. Here, we performed a large-scale glycan array screen with MuV hemagglutinin-neuraminidase (MuV-HN) attachment proteins by using 600 types of glycans from The Consortium for Functional Glycomics Protein-Glycan Interaction Core in an effort to find new glycan receptor motif(s). According to the results of the glycan array, we successfully determined the crystal structures of MuV-HN proteins bound to newly identified glycan motifs, sialyl LewisX (SLeX) and the oligosaccharide portion of the GM2 ganglioside (GM2-glycan). Interestingly, the complex structures showed that SLeX and GM2-glycan share the same configuration with the reported trisaccharide motif, 3'-sialyllactose (3'-SL), at the binding site of MuV-HN, while SLeX and GM2-glycan have several unique interactions compared with those of 3'-SL. Thus, MuV-HN protein can allow an additional spatial modification in GM2-glycan and SLeX at the second and third carbohydrates from the nonreducing terminus of the core trisaccharide structure, respectively. Importantly, MuV entry was efficiently inhibited in the presence of 3'-SL, SLeX, or GM2-glycan derivatives, which indicates that these motifs can serve as MuV receptors. The ?2,3-sialylated oligosaccharides, such as SLeX and 3'-sialyllactosamine, are broadly expressed in various tissues, and GM2 exists mainly in neural tissues and the adrenal gland. The distribution of these glycan motifs in human tissues/organs may have bearing on MuV tropism.IMPORTANCE Mumps virus (MuV) infection is characterized by parotid gland swelling and can cause pancreatitis, orchitis, meningitis, and encephalitis. MuV-related hearing loss is also a serious complication because it is usually irreversible. MuV outbreaks have been reported in many countries, even in high-vaccine-coverage areas. MuV has tropism toward glandular tissues and the central nervous system. To understand the unique MuV tropism, revealing the mechanism of receptor recognition by MuV is very important. Here, using a large-scale glycan array and X-ray crystallography, we show that MuV recognizes sialyl LewisX and GM2 ganglioside as receptors, in addition to a previously reported MuV receptor, a trisaccharide containing an ?2,3-linked sialic acid. The flexible recognition of these glycan receptors by MuV may explain the unique tropism and pathogenesis of MuV. Structures will also provide a template for the development of effective entry inhibitors targeting the receptor-binding site of MuV.
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Project description:We evaluate the individual growth of 8 mutants of Sendai virus in the competitive condition under the cultured cells. We also evalate the growth of 6 mutants of mumps virus in the similar competitive condition.
2019-03-21 | GSE128625 | GEO
Project description:We report the genetic plasticity of Sendai virus and mumps virus. We introduced insertional mutation in the virus genome and checked fitness by comparing distribution of mutans in passage 1 and passage 2.
2019-02-01 | GSE125257 | GEO
Project description:Mumps is an acute and self-limiting disease characterized by parotitis, however in some cases it leads to aseptic meningitis, deafness, encephalitis and orchitis, which is a serious health concern. MMR vaccination was successful in eradicating the disease however, recent reports question the efficacy of MMR vaccine and countless outbreaks are observed in vaccinated populations throughout the world. Lack of specific treatment methods for mumps infection and inefficiency of MMR vaccine in vaccinated populations accentuates the need for the development of novel drugs to control mumps virus mediated serious infections. It was with this backdrop of information that the anti-mumps virus activity of Mimosa pudica was evaluated. Suspected mumps cases were collected to isolate a standard mumps virus by systematic laboratory testing which included IgM antibody assays, virus isolation, RT-PCR and phylogenetic analysis. The virus was quantified by TCID50 assay and anti-mumps virus property was evaluated by CPE reduction assay and cytotoxicity of the extract was measured by MTT assay and phytochemical analysis was done by gas chromatography-mass spectroscopy. The RT-PCR and phylogenetic tree analysis of the SH gene sequence of the clinical isolate showed it to be mumps virus genotype C. 150 ?g/ml concentration of M. pudica completely inhibited mumps virus and the drug was found to be non-toxic up to 2 mg/ml. M. pudica was thus found to be a potent inhibitor of MuV.
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Project description:Recombinant Mumps viruses grown on Vero cells (Cercopithecus aethiops). Detection and quantification of defective viral genomes (DVGs) in high throughput sequencing data using DVG-profiler, a novel post sequence alignment processing algorithm.
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Project description:PVC-211 murine leukemia virus (MuLV) is a neuropathogenic variant of Friend MuLV (F-MuLV). Previous studies from our laboratory demonstrated that unlike the parental F-MuLV, PVC-211 MuLV can infect rat brain capillary endothelial cells efficiently and that it has acquired genetic changes responsible for its expanded cellular tropism. To determine if PVC-211 MuLV also has expanded its host range, we tested its infectivity on Chinese hamster ovary-derived CHO-K1 cells, which are generally resistant to ecotropic MuLV. The results indicated that PVC-211 MuLV, but not F-MuLV, was highly infectious for CHO-K1 cells. Studies using glycosylation inhibitors and glycosylation mutants of CHO-K1 cells, as well as interference studies, suggested that PVC-211 MuLV has acquired the ability to interact with the ecotropic MuLV receptor on CHO-K1 cells that has undergone glycosylation-dependent modification. Using chimeric viruses between PVC-211 MuLV and F-MuLV, we were able to localize the viral genetic element crucial for CHO-K1 cell tropism within the env gene of PVC-211 MuLV and show that glycine at position 116 and lysine at position 129 of the envelope glycoprotein SU were important. These viral determinants also appear to confer tropism for other hamster cells resistant to ordinary ecotropic MuLVs. Further studies on the interaction between PVC-211 MuLV and the receptor on hamster cells may provide novel insights into the molecular mechanisms for receptor recognition and binding by viral envelope glycoproteins.
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Project description:Giardiavirus (GLV) utilizes an internal ribosome entry site (IRES) for translation initiation in the early branching eukaryote Giardia lamblia. Unlike most of the viral IRESs among higher eukaryotes, which localize primarily within the 5'-untranslated region (UTR), the GLV IRES comprises 253 nts of 5'UTR and the initial 264 nts in the open-reading-frame (ORF). To test if GLV IRES also functions in higher eukaryotic systems, we examined it in rabbit reticulocyte lysate (RRL) and found that it functions much less efficiently than the IRES from the Encephalomyocarditis virus (EMCV) or Cricket paralysis virus (CrPV). In contrast, both EMCV-IRES and CrPV-IRESs were inactive in transfected Giardia cells. Structure-function analysis indicated that only the stem-loop U5 from the 5'UTR and the stem-loop I plus the downstream box (Dbox) from the ORF of GLV IRES are required for limited IRES function in RRL. Edeine, a translation initiation inhibitor, did not significantly affect the function of GLV IRES in either RRL or Giardia, indicating that a pre-initiation complex is not required for GLV IRES-mediated translation initiation. However, the small ribosomal subunit purified from Giardia did not bind to GLV IRES, indicating that additional protein factors may be necessary. A member of the helicase family IBP1 and two known viral IRES binding proteins La autoantigen and SRp20 have been identified in Giardia that bind to GLV IRES in vitro. These three proteins could be involved in facilitating small ribosome recruitment for initiating translation.
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