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Sundaravaradan, Vasudha. "Molecular Mechanism of HIV-1 Infection: Role of Viral and Host Determinants." Diss., Tucson, Arizona : University of Arizona, 2006. http://etd.library.arizona.edu/etd/GetFileServlet?file=file:///data1/pdf/etd/azu%5Fetd%5F1685%5F1%5Fm.pdf&type=application/pdf.
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Sumpter, Rhea Myers Jr. "Viral and host genetic determinants of hepatitis C virus persistence and interferon resistance." Access to abstract only; dissertation is embargoed until after 5/16/2007, 2004. http://www4.utsouthwestern.edu/library/ETD/etdDetails.cfm?etdID=170.
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McCarthy, Kevin Raymond. "Viral and Host Determinants of Primate Lentivirus Restriction by Old World Primate TRIM5alpha Proteins." Thesis, Harvard University, 2014. http://nrs.harvard.edu/urn-3:HUL.InstRepos:13065027.
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The host restriction factor TRIM5α mediates a post-entry, pre-integration block to retroviral infection that depends upon recognition of the viral capsid by the TRIM5α PRYSPRY domain. The two predominant alleles of rhesus macaque TRIM5α (rhTRIM5αQ and rhTRIM5αTFP) restrict HIV 1, but cannot restrict the macaque-adapted virus SIVmac239. To investigate how TRIM5α recognizes retroviral capsids, we exploited the differential sensitivities of these two viruses to identify gain-of-sensitivity mutations in SIVmac239, and we solved the structure of the SIVmac239 capsid N-terminal domain. When mapped onto this structure, single amino acid substitutions affecting both alleles were in the β-hairpin. In contrast, mutations specifically affecting rhTRIM5αTFP surround a highly conserved patch of amino acids that is unique to capsids of primate lentiviruses. This "patch" sits at the junction between the binding sites of multiple cellular cofactors (cyclophilin A, Nup-358 cyclophilin A-like domain, Nup-153 and CPSF6). Differential restriction of these alleles is due to a Q/TFP polymorphism in the first variable loop (V1) within the PRYSPRY domain. Q reflects the ancestral state (present in the last common ancestor of Old World primates) and has remained unmodified in all but one lineage of African monkeys, the Cercopithecinae. While Q-alleles can be found among some Cercopithecinae primates, in others Q has been replaced by a G or overwritten by a two amino acid insertion (giving rise to TFP in macaques). In one lineage, the Q to G substitution was later followed by an adjacent 20 amino acid duplication. We found that these modifications in TRIM5α specifically impart the ability to restrict Cercopithecinae SIVs without altering β-hairpin recognition. At least twice Cercopithecinae TRIM5αs independently evolved to target the same conserved patch of amino acids in capsid. Based on these findings, we propose that the β-hairpin is a retrovirus associated molecular pattern widely exploited by TRIM5α proteins, while recognition of the cofactor binding region was driven by the emergence of the ancestors of modern Cercopithecinae SIVs. Distribution on the Cercopithecinae phylogenetic tree indicates that selection for these changes in TRIM5α V1 began 11-16 million years ago, suggesting that primate lentiviruses are at least as ancient.
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Wellensiek, Brian Philip. "Molecular Mechanisms of HIV-1 Infection: Viral and Host Determinants in Transmission and Pathogenesis." Diss., The University of Arizona, 2007. http://hdl.handle.net/10150/195132.
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HIV-1 vertical transmission is the predominant cause of AIDS in children. In addition, HIV-1 infected infants have a higher viral load and progress to AIDS more rapidly than infected adults. However, the molecular mechanisms of HIV-1 vertical transmission and pathogenesis are not known. Work performed in this laboratory has shown transmission of minor genotypes with R5 phenotypes, more heterogeneity associated with transmission and a higher replication and gene expression of HIV-1 in neonatal than adult cells. In this dissertation, I have made advancements by characterizing the HIV-1 gag nucleocapsid gene, that plays a pivotal role in HIV-1 lifecycle, from six mother-infant pairs and found that there was a low degree of viral heterogeneity and a high conservation of functional domains for biological activity and CTL response. With respect to differential mechanisms of HIV-1 infection in neonatal vs. adults cells, 468 HIV-1 integration sites were characterized in the T-lymphocytes and monocyte-derived-macrophages from 5 donors of infant and adult blood. Several functional classes of genes were identified by gene ontology to be over represented, including genes for cellular components, maintenance of intracellular environment, enzyme regulation, cellular metabolism, catalytic activity and cation transport. Numerous potential transcription factors binding sites at the site of integration were identified. Furthermore, the genes at integration site, transcription factors potentially binding upstream of HIV-1 promoter and factors that assist HIV-1 integration were found to be expressed at higher levels in cord than adult cells. These results may help explain a higher HIV-1 gene expression and replication in cord compared with adult cells. Finally, I have also made progress in the development of new and novel antivirals by showing that CD4-mimetic miniproteins significantly inhibited HIV-1 entry and replication in T-cell lines and primary blood mononuclear cells. In addition, several compounds from the crude extracts of endophytic fungi found in desert plants were able to inhibit HIV-1 replication in T-cell lines. Taken together, the results from this dissertation provide new insights into understanding the mechanisms of HIV-1 vertical transmission and HIV-1 gene expression and replication in infants, as well as provide new possibilities for anti-retroviral drug development.
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Bruland, Torunn. "Studies of early retrovirus-host interactions. Viral determinants for pathogenesis and the influence of sex on the susceptibility to Friend murine leukaemia virus infection." Doctoral thesis, Norwegian University of Science and Technology, Faculty of Medicine, 2003. http://urn.kb.se/resolve?urn=urn:nbn:no:ntnu:diva-534.
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<p>The studies in the present thesis sought to define virus and host factors that can influence on the susceptibility to murine retrovirus infection. In addition, we wanted to study possible correlations between events of early infection and subsequent disease progression. For an extensive discussion of the major findings, the reader is referred to papers I-IV. The following section will give a general discussion concerning 1) some methodological aspects; 2) the course of FIS-2 infection; 3) determinants responsible for erythroleukaemia; 4) determinants responsible for immunosuppression; and, 5) does sex matter?</p>
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Mahadevan, Geetha B. "Viral suppression of host defenses." Link to electronic thesis, 2004. http://www.wpi.edu/Pubs/ETD/Available/etd-0507104-110551.
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Muenzner, Julia. "Viral subversion of host cell membrane trafficking." Thesis, University of Cambridge, 2017. https://www.repository.cam.ac.uk/handle/1810/267890.
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Enveloped viruses acquire their membrane coat from the plasma membrane or intracellular organelles and rely on cellular machinery to facilitate envelopment and egress of virus progeny. This thesis examines egress-related interactions between host cell factors and proteins of two different enveloped viruses: hepatitis D virus (HDV) and herpes simplex virus 1 (HSV-1). HDV is a small RNA virus causing fulminant hepatitis or severely aggravating cirrhosis and hepatocellular carcinoma. HSV-1 is a large DNA virus infecting epithelial and neuronal cells. Infection with HSV-1 not only triggers the development of recurring sores on oral or genital mucosa, but can also cause severe disease in neonates and immunocompromised patients. The interaction between the large antigen of HDV (HDAg-L) and the N-terminal domain (NTD) of clathrin, a protein crucial for endocytosis and intracellular vesicular trafficking, was examined by structural, biochemical and biophysical techniques. Co-crystal structures of NTD bound to HDAg-L peptides derived from different HDV genotypes revealed that HDV interacts with multiple binding sites on NTD promiscuously, prompting re-evaluation of the binding between cellular peptides and NTD. Surprisingly, co-crystal structures and pull-down capture assays showed that cellular peptides containing clathrin-binding motifs can also bind multiple sites on the surface of NTD simultaneously. In addition, the structures of viral and cellular peptides bound to NTD enabled the molecular characterization of the fourth peptide binding site on NTD, the “Royle box”, and led to the identification of a novel binding mode at the “arrestin box” peptide binding site on NTD. The work in this thesis therefore not only identifies the molecular basis of HDV:clathrin interactions, but also furthers our understanding of basic clathrin biology. Even though many HSV-1 proteins have been implicated in the envelopment and egress of viral particles, only few interactions between HSV-1 and cellular proteins promoting these processes have been described. Therefore, the HSV-1 proteins gE, UL21 and UL56 were selected and characterized bioinformatically and/or biochemically. Cellular proteins interacting with UL56 were identified by yeast two-hybrid screening and quantitative mass spectrometry. Co-immunoprecipitation and pull-down experiments confirmed the Golgi-trafficking protein GOPC, components of the mammalian trafficking protein particle complex, and the ubiquitin ligase NEDD4 as novel binding partners of UL56, thereby suggesting exciting new avenues for the investigation of cellular mechanisms contributing to HSV-1 envelopment and egress.
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Carney, Jennifer. "Viral Determinants of Flavivirus Neurotropism in Humans." Thesis, University of Liverpool, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.526956.
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Seaberg, Bonnie Lee. "Host factors involved in viral movement through plants." Thesis, [College Station, Tex. : Texas A&M University, 2008. http://hdl.handle.net/1969.1/ETD-TAMU-3282.
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Edge, David. "Identification of host factors controlling plant viral movement." Thesis, University of East Anglia, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.398793.
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Nilsson, Benjamin Erik. "Viral and host factors regulating influenza virus replication." Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:b8953952-e6d5-4f6d-a7ba-cd55277611d1.
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Avian influenza A viruses typically do not replicate very efficiently when exposed to a mammalian host species. One of the reasons for this is the low activity of the viral RNA-dependent RNA polymerase of avian influenza viruses in mammalian cells. This host restrictive effect can be overcome by adaptive mutations in the avian polymerase, many of which are found in the 627-domain of the PB2 polymerase subunit. Deletion of the 627-domain revealed that this domain is not required for enzymatic functions of the polymerase in vitro, but that it essential for viral replication in a cellular environment in a nucleoprotein-independent manner. While the 627-domain is not necessary for viral RNA synthesis, it was demonstrated that it is involved in mediating encapsidation of nascent replication products. Recently the host factor ANP32A was shown to be the main determinant of host range restriction of the viral polymerase. It was demonstrated that during viral infections ANP32A interacts with KPNA2, a host factor strongly linked to host range restriction of the viral polymerase. It was also revealed that avian polymerases specifically are restricted in vRNA synthesis, a defect that was reversed in the presence of avian ANP32A. ANP32A was shown to be an enhancer of vRNA synthesis in vitro. Viral polymerase-polymerase interactions have been reported previously and presumably fulfil several essential functions during viral replication. Here the potential interaction interfaces of two different polymerase dimers were investigated and a role of polymerase dimers in replication and in trans-activation of cRNA-bound polymerases was found. RNA-binding proteins are essential for RNA metabolism and therefore cell physiology. It has been reported that the RNA-binding proteome responds to biological stimuli. Here the response of the RNA-binding proteome to influenza virus infection was investigated using an in vivo UV crosslinking interactome capture technique. It was demonstrated that the RNA-binding proteome is significantly altered and that this effect is independent of protein abundance. Several host RNA-binding proteins were identified that change their RNA-binding behaviour and that could have pro- or antiviral functions during influenza virus infection.
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Mistry, Nitesh. "Human papillomavirus tropism : determinants of viral tissue specificity." Doctoral thesis, Umeå : Univ, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1149.
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Opavsky, Mary Anne. "Determinants of host susceptibility to coxsackieviral myocarditis." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/NQ63730.pdf.
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McCall, Laura-Isobel. "Parasite and host determinants of visceral leishmaniasis." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=116947.
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Leishmaniasis is a neglected tropical disease caused by Leishmania protozoa and transmitted by a sand fly vector. There are three main disease manifestations: self-healing but scarring cutaneous leishmaniasis, mucocutaneous leishmaniasis with destruction of the mucosal tissues in the nose, mouth and throat, and visceral leishmaniasis in which parasites disseminate to the bone marrow, liver and spleen, leading to high fever, hepatosplenomegaly, wasting, and death in the absence of treatment. Visceral leishmaniasis is the second most lethal tropical disease after malaria. A key question of leishmaniasis research is why some Leishmania species such as Leishmania major remain at the site of the sand fly bite in cutaneous leishmaniasis while other species such as Leishmania donovani metastasize to visceral organs. The overall goal of this thesis was to identify factors involved in visceral disease pathogenesis. We hypothesized that parasite factors play a determining role in visceral disease and that host characteristics are also involved. First, we examined the function of A2, a protein family already implicated in L. donovani visceralization. A2 is shown to protect against heat shock and oxidative stress, key host defences against visceral leishmaniasis. Second, we studied an atypical L. donovani clinical isolate from Sri Lanka that causes cutaneous rather than visceral leishmaniasis, comparing it to a clinical isolate from a Sri Lankan visceral leishmaniasis patient. Although both strains were equally infective to macrophages in vitro, they caused significantly different disease phenotypes in vivo in mice: only the cutaneous isolate caused footpad swelling while only the visceral isolate led to significant liver and spleen parasitemia. A2 expression was lower in the cutaneous isolate and ectopically expressing an additional A2 gene in the cutaneous isolate partially restored virulence in the visceral organs. Therefore, parasite factors are a key determinant of visceral disease. However, host characteristics and history can also influence the development of visceral leishmaniasis. In Sri Lanka, cutaneous leishmaniasis caused by L. donovani is frequent while visceral disease is rare. We show here that immunization with a cutaneous clinical isolate is associated with a mixed Th1/Th2 response and protects BALB/c mice from visceral leishmaniasis, providing a possible rationale for the low incidence of visceral leishmaniasis in Sri Lanka. Overall, these results represent significant progress into the determinants of visceral leishmaniasis and in particular on the role of the virulence factor A2. A novel candidate for a live-attenuated vaccine against visceral leishmaniasis is also presented here. Given the lack of a human vaccine for leishmaniasis and the limitations of the current treatment options, this work could have a significant impact on disease management in Sri Lanka and on vaccine development.<br>Les leishmanioses sont un groupe de maladies tropicales causées par le protozoaire Leishmania et transmises par la piqûre de phlébotomes. Les leishmanioses peuvent être divisées en trois formes cliniques: leishmaniose cutanée qui guérit sans traitement mais laisse des cicatrices, leishmaniose mucocutanée avec destruction des muqueuses du nez, de la bouche et de la gorge, et leishmaniose viscérale où les parasites quittent le site de la piqûre et se propagent jusqu'à la moelle osseuse, le foie et la rate. Les symptômes de la leishmaniose viscérale sont une forte fièvre et une hepatosplénomégalie, et ceci peut être fatal en l'absence de traitement. La leishmaniose viscérale a le deuxième plus haut taux de mortalité parmi les maladies tropicales, après la malaria. Un des enjeux majeurs de la recherche sur les leishmanioses est de comprendre pourquoi certaines espèces de Leishmania comme Leishmania major restent au site de la piqûre des phlébotomes dans le cas des leishmanioses cutanées, tandis que Leishmania donovani se propage jusqu'aux organes viscéraux. Le but de cette thèse est d'identifier les facteurs impliqués dans la pathogénèse de la leishmaniose viscérale. L'hypothèse de recherche est que les caractéristiques du parasite jouent un rôle principal dans la leishmaniose viscérale et que les caractéristiques de l'hôte sont également importantes. Nous examinons la fonction de A2, une famille de protéines qui sont impliquées dans la viscéralisation de L. donovani. Nous montrons que A2 protège contre le choc thermique et contre les oxydants, deux défenses clé du système immunitaire contre la leishmaniose viscérale. Ensuite, nous étudions un isolat clinique atypique de L. donovani venu du Sri Lanka qui cause des leishmanioses cutanées au lieu de provoquer des leishmanioses viscérales. Nous comparons cet isolat à un isolat clinique provenant d'un patient sri lankais souffrant de leishmaniose viscérale. Quoique ces deux isolats soient tout aussi infectieux l'un que l'autre in vitro, ils causent des symptômes différents in vivo: seul l'isolat cutané cause l'enflure du coussinet plantaire après injection sous-cutanée chez les souris et seul l'isolat viscéral peut se multiplier dans le foie et la rate. Les niveaux de A2 sont plus bas dans l'isolat cutané et nous démontrons que cela constitue un facteur déterminant de son atténuation. Ces résultats prouvent donc que les caractéristiques du parasite ont une influence majeure dans la pathogénèse des leishmanioses viscérales. Cependant, les caractéristiques de l'hôte et son historique médical peuvent également influencer le développement de cette maladie. Les leishmanioses cutanées sont beaucoup plus fréquentes au Sri Lanka que les leishmanioses viscérales. Nous prouvons ici que la vaccination avec l'isolat cutané mène à une réponse du système immunitaire de type Th1/Th2 mixte et protège contre la leishmaniose viscérale dans un modèle in vivo d'infection de souris BALB/c. Ces résultats proposent un modèle pour expliquer la rareté de la leishmaniose viscérale au Sri Lanka. En conclusion, ces résultats éclaircissent plusieurs facteurs impliqués dans le développement de la leishmaniose viscérale et en particulier le rôle du facteur de virulence A2. Nous présentons également un nouveau candidat de vaccin atténué contre la leishmaniose viscérale. Etant donné l'absence de vaccin humain pour cette maladie et les limites des traitements actuels, cette étude pourrait avoir un impact majeur sur la santé publique au Sri Lanka et sur le développement de vaccins contre la leishmaniose viscérale.
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Buendia, Patricia. "Phylogenetic analysis of within-host serially-sampled viral data." FIU Digital Commons, 2006. http://digitalcommons.fiu.edu/etd/2019.
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The primary goal of this dissertation is the study of patterns of viral evolution inferred from serially-sampled sequence data, i.e., sequence data obtained from strains isolated at consecutive time points from a single patient or host. RNA viral populations have an extremely high genetic variability, largely due to their astronomical population sizes within host systems, high replication rate, and short generation time. It is this aspect of their evolution that demands special attention and a different approach when studying the evolutionary relationships of serially-sampled sequence data. New methods that analyze serially-sampled data were developed shortly after a groundbreaking HIV-1 study of several patients from which viruses were isolated at recurring intervals over a period of 10 or more years. These methods assume a tree-like evolutionary model, while many RNA viruses have the capacity to exchange genetic material with one another using a process called recombination.
A genealogy involving recombination is best described by a network structure. A more general approach was implemented in a new computational tool, Sliding MinPD, one that is mindful of the sampling times of the input sequences and that reconstructs the viral evolutionary relationships in the form of a network structure with implicit representations of recombination events. The underlying network organization reveals unique patterns of viral evolution and could help explain the emergence of disease-associated mutants and drug-resistant strains, with implications for patient prognosis and treatment strategies. In order to comprehensively test the developed methods and to carry out comparison studies with other methods, synthetic data sets are critical. Therefore, appropriate sequence generators were also developed to simulate the evolution of serially-sampled recombinant viruses, new and more through evaluation criteria for recombination detection methods were established, and three major comparison studies were performed. The newly developed tools were also applied to “real” HIV-1 sequence data and it was shown that the results represented within an evolutionary network structure can be interpreted in biologically meaningful ways.
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Wong, Tse Yuan. "Host protein manipulation as a mechanism in viral cardiomyopathy." Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/43095.
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Viral myocarditis, the inflammation of myocardium initiated by viral infection, is an important cause of mortality in neonates and children. In addition, it is a precursor to dilated cardiomyopathy (DCM). To date, no effective therapy is available for viral myocarditis/DCM. Coxsackievirus B3 (CVB3) is an important human pathogen of viral myocarditis. Extensive research efforts on CVB3 have broadened our understanding of the virus-host protein interactions. However, the pathogenesis of coxsackievirus-induced myocarditis is not fully understood. The objective of this dissertation is to explore the role of host protein manipulation in coxsackieviral replication and pathogenicity. My hypotheses are that (1) coxsackievirus hijacks host’s cellular autophagy mechanism to facilitate its own replication; and (2) the serum response factor (SRF) is cleaved by viral protease 2A during coxsackievirus infection and contributes to impaired myocardial function and progression to DCM. For project 1, I demonstrated that CVB3 manipulates the host autophagy pathway to supplement viral replication. Autophagy is an evolutionary conserved homeostatic mechanism in eukaryotes that degrades and recycles long-lived cytoplasmic proteins, as well as damaged organelles. The hallmark of autophagy is the formation of double-membrane vesicles known as autophagosomes. I provided the initial evidence that CVB3 infection induces the formation of autophagosomes. Up-regulation of autophagosome formation enhances CVB3 replication, whereas downregulation of autophagy pathway reduces CVB3 replication. My results help clarify the nature of the intracellular membranes previously shown to be required for viral replication. For project 2, I demonstrated that CVB3 manipulates SRF expression via protein cleavage. SRF is a transcription factor vital for the expression of cardiac contractile/regulator genes, as well as gene silencing microRNAs. Cardiac-specific knockout of SRF in adult transgenic mice results in disruption of cardiac gene expression and development of severe DCM. I showed that SRF is cleaved in CVB3-infected mouse hearts and cardiomyocytes. Further studies revealed that SRF is cleaved at the 327 amino acids position by CVB3-encoded protease 2A. I demonstrated that SRF cleavage contributes to DCM by abolishing the transactivation property of SRF and generating dominant-negative SRF-truncates. Taken together, these novel viral strategies bridged existing knowledge and may serve as therapeutic targets for viral myocarditis/DCM.
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Gramoustianou, Evangelia Sophia. "Viral and host gene expression during human cytomegalovirus infection." Thesis, University College London (University of London), 2005. http://discovery.ucl.ac.uk/1444419/.
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HCMV infection is usually asymptomatic in immunocompetent hosts, but serious disease can occur in immunocompromised individuals and in congenitally infected newborns. The importance of virus fitness determinations became evident in 1976, when it was proposed that the infecting strain of HCMV is important for clinical outcome, along with the intensity and duration of viral replication. HCMV strains exhibit different levels of virulence in vivo, depending on their passage history in cell culture. High and low passage HCMV strains exhibit tropism differences in vitro, suggesting that different tissue tropism may occur in vivo. In addition, approximately 13kb of novel DNA sequences located near the right edge of the unique long component of the genome has been identified in Toledo and clinical strains. This region (UL/b') encodes several open reading frames, which are missing from the high passage laboratory-adapted variants of Towne and AD 169 and are thought to play important roles in pathogenesis. One of the aims of this thesis was to determine the replication dynamics of different HCMV strains in vitro as well as compare their ability to bind to cells and mediate cell-to-cell spread of infection using pair-wise competition experiments in cell culture. AD 169 was shown to replicate better than Toledo in fibroblasts. Furthermore, assessment of the replication of Toledo in a different cell type, HUVEC, indicated that the virus replicated to higher levels in fibroblasts. Towne was found to bind to HEL cells with higher affinity compared to AD 169. The results showed phenotypic differences between high and low passaged HCMV variants and also illustrated that fitness differences between them are variable and highly dependent upon the status of the virus inoculum. To begin to understand the complex relationship between tissue tropism, virulence and HCMV genome composition, a DNA microarray approach was developed to examine host and HCMV gene expression during the productive infection of two distinct cell lines, fibroblasts and endothelial cells. The results showed that genes wifrojn tye fPSIPp were expressed in a cell type-specific fashion. Ip the context of host cell gene expression, cell type-specific host gene transcriptional changes were observed, reflecting different viral modulation of distinct cell type environments. The results provided potential insight into the function of genes encoded in the UL/b' region. Of particular note was that transcriptional changes frequently occurred in genes associated with pathways involved in the pathology of HCMV in the human host.
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Lissauer, Samantha Mary. "Modelling hepatitis C viral host interaction and co-infection." Thesis, University of Birmingham, 2018. http://etheses.bham.ac.uk//id/eprint/8774/.
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Hepatitis C Virus (HCV) is a clinically important infection that leads to chronic liver disease and Human Immunodeficiency Virus (HIV) co-infected patients have more rapid progression to severe liver disease and show higher rates of HCV vertical transmission. Hepatocytes are a highly differentiated cell type and support low level HCV replication. Most studies of the viral life cycle use de-differentiated hepatoma cell lines, which are highly permissive. The mechanism behind this difference is poorly understood. We show that dimethylsulfoxide (DMSO) differentiated Huh-7 cells have a 100-fold reduction in permissivity to HCV infection. We confirm that these cells are differentiated and upregulate key liver specific markers including miR122. They are metabolically active and have intact innate signaling pathways in response to infection. We observed a 10-fold reduction in the initiation of replication and a 10-fold loss in extra-cellular particle infectivity. In contrast cell-to-cell dissemination rates were comparable and cell-contact dependent infection of differentiated cells can overcome the restrictions seen in cell-free infection. HCV cell-to-cell transmission can also be mediated by other cell types. T cells are the primary cell supporting HIV-1 infection. We have shown that HCV can bind primary and immortalized T cells and trans-infect hepatoma cells. This requires replicating HIV but is independent of co-receptor engagement. HIV-1 infection of CD4+ T cells induces a significant increase in HCV trans-infection by increased viral binding. T cells provide a vehicle for HIV-1 to promote HCV infectivity, transmission and persistence.
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Berthold, François. "Grapevine fanleaf virus replication : viral proteins and host factors." Strasbourg, 2015. http://www.theses.fr/2015STRAJ086.
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Cootes, Taylor Ann. "Dietary regulation of the host response to viral infection." Thesis, The University of Sydney, 2022. https://hdl.handle.net/2123/28614.
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Host factors, such as genetics and aging, are known to regulate the severity of influenza. However, the role of environmental factors in the viral infection remains poorly defined. By altering individual nutrition components or energy density, animal studies have clearly demonstrated that diet modulates the outcome to influenza in mice. However, it remains unclear whether energy-balanced diets, known to be sufficient in supporting the health of naïve animals, are adequate in mediating the survival of the infected host. This thesis work was set to investigate whether diet quality, independent of energy and macronutrient intake, controls the outcome of influenza virus infection in mice and the mechanisms that underlie it.
In Chapter 3, I determined whether mice fed on two commonly used laboratory diets, chow and AIN93G, are equally efficient in supporting host defence against IAV infection. I observed that mice fed on AIN93G exhibited increased mortality following the infection. Interestingly, the increased susceptibility was not due to impaired induction of antiviral immunity or pathogen control but instead due to perturbed physiological function and failure to restore homeostasis following infection. These findings reveal that isocaloric diets with differing qualitative composition regulates host fitness, rather than pathogen clearance.
To understand the mechanisms underlying the altered physiological function in AIN93G-fed mice, I elucidated the transcriptional responses in organs important for regulating vital physiological functions, such as body temperature and appetite, in chapter 4. While displaying comparable gene signatures before infection, chow and AIN93G-fed mice exhibited distinct transcriptomic profiles following infection, particularly in the hypothalamus and BAT. While the expression of genes relating to the immune response were comparable between in chow and AIN93G-fed mice, the expression of the genes involving cell differentiation was altered significantly in latter animals, uncovering a potential transcriptional mechanism for the dysregulated thermoregulation observed in AIN93G-fed mice.
In chapter 5, I demonstrated that mice maintained on purified diets with varying protein and carbohydrate ratios showed differential susceptibility to infection, thereby demonstrating definitively that the dietary variations in energy- balanced diets are sufficient in altering the outcome of influenza virus infection. Cytokines have been established as being responsible for the perturbed physiological functioning that occurs during infection. In the second part of this chapter, I investigate the role of IFN-gamma in regulating host fitness in mice fed purified diets and demonstrated that IFN-gamma receptor deficient mice fed on AIN93G are completely protected from influenza virus infection, revealing a diet-dependent detrimental function for IFN-gamma to influenza.
These findings reveal diet as a crucial environmental factor that determines host fitness and uncover mechanisms underlying the preservation of physiological homeostasis necessary for survival to influenza virus infection.
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King, Benjamin. "Arenavirus Transcription, Replication, and Interaction with Host-Cellular Components." ScholarWorks @ UVM, 2018. https://scholarworks.uvm.edu/graddis/830.
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Arenaviruses are enveloped negative-strand RNA viruses that cause significant human disease. Despite decades of research, it is still unclear how these viruses establish a lifelong, asymptomatic infection in their rodent hosts while infection of humans often results in severe disease. Unable to enter a state of bona fide latency, the transcription and replication of the viral genomic RNA is likely highly regulated in time and subcellular space. Moreover, we hypothesize that the viral nucleoprotein (NP), responsible for the encapsidation of the viral RNA and the most highly expressed viral gene product, plays a key role in the regulation of the viral gene expression program. Further, exploring host-virus interactions may elucidate the basic aspects of arenavirus biology and how they cause such severe disease in humans. To explore these questions in greater detail, this dissertation has pursued three main avenues.
First, to better understand lymphocytic choriomeningitis mammarenavirus (LCMV) genome replication and transcription at the single-cell level, we established a high-throughput, single-molecule (sm)FISH image acquisition and analysis pipeline and followed viral RNA species from viral entry through the late stages of persistent infection in vitro. This work provided support for a cyclical model of persistence where individual cells are initially transiently infected, clear active infection, and become re-infected from neighboring reservoir cells within the population.
Second, we used FISH to visualize viral genomic RNA to describe the subcellular sites where LCMV RNAs localize during infection. We observed that, viral RNA concentrates in large subcellular structures located near the cellular microtubule organizing center and colocalizes with the early endosomal marker Rab5c and the viral glycoprotein in a proportion of infected cells. We propose that the virus is using the surface of a cellular membrane bound organelle as a site for the pre-assembly of viral components including genomic RNA and viral glycoprotein prior to their transport to the plasma membrane where new particles will bud.
Last, we used mass spectrometry to identify human proteins that interact with the NPs of LCMV and Junín mammareanavirus (JUNV) strain Candid #1. We provided a detailed map of the host machinery engaged by arenavirus NPs, and in particular, showed that NP associates with the double-stranded RNA (dsRNA)-activated protein kinase (PKR), a well-characterized antiviral protein that inhibits cap-dependent protein translation initiation via phosphorylation of eIF2α. We demonstrated that JUNV antagonizes the antiviral activity of PKR completely, effectively abrogating the antiviral activity of this surveillance pathway.
In sum, the work composing this dissertation has given us fresh insight into how arenaviruses establish and maintain persistence; the nature of the subcellular site where viral genomic RNA is transcribed, replicated, and assembled with other viral components; and a global view of the cellular machinery hijacked by the viral nucleoprotein. This work improves our basic understanding of the arenavirus life cycle and may suggest novel antiviral therapeutic targets that could be exploited in the future.
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Baillie, Andrew James. "Cellular and viral determinants for hepatitis C virus replication." Thesis, Imperial College London, 2010. http://hdl.handle.net/10044/1/6865.
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The recent discovery of an HCV isolate which replicates in cell culture has opened up opportunities to study the full viral life cycle in vitro. This genotype 2a isolate (JFH-1) and its derivatives are the only ones known to replicate efficiently in cell culture, and recent work has indicated that viral determinants for efficient replication may lie in the non-structural protein coding region of the genome. In this thesis chimaeric JFH-1 virus containing full length NS3, NS3 helicase and NS3 protease sequences from genotype 1a and 1b were constructed. The replication efficiencies of chimaeric viruses were tested in cell culture, and were shown not to replicate, indicating that vital viral determinants for JFH-1 replication exist in NS3. The JFH-1 model also provides the opportunity to study the effect of the full viral life cycle on the host cell. Microarray analyses were performed to identify gene expression changes in Huh7 and Huh7.5 cells that had been infected with JFH-1 for 6, 12, 18, 24 and 48 hours. A large number of host genes were found to be regulated during JFH-1 infection, including those involved in lipid metabolism, oxidative stress, apoptosis and intracellular transport. The microarray data were validated by quantitative PCR analyses of separate infection experiments. A selection of the most highly regulated genes was assessed for their necessity to HCV replication by RNA interference studies. The knockdown by siRNA of genes ABLIM3, SPTLC3 and CYP1A1 resulted in significant impairment of HCV replication. The knockdown by siRNA of gene TXNIP (thioredoxin interacting protein) resulted in up to 90% reduction in HCV replication. This is a novel finding which may be of importance to the study of HCV as TXNIP plays roles in oxidative stress, lipid metabolism and glucose metabolism, all of which have potential to influence the HCV lifecycle. Magnetic resonance spectroscopy indicated a change in levels of choline metabolites in JFH-1 infected cells, which has implications for the aspects of the HCV lifecycle associated with lipid membranes and other lipid structures.
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Abel, Svenja [Verfasser], Siobhan O. Akademischer Betreuer] Burns, and Bodo [Akademischer Betreuer] [Grimbacher. "The characteristics of viral skin infections in the immunocompromised host." Freiburg : Universität, 2019. http://d-nb.info/1197536426/34.
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Jenner, Richard Gareth. "Viral and host gene expression in human B-cell lymphoma." Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.398336.
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Crill, Wayne Douglass. "Experimental evolution and molecular basis of host-specific viral adaptation /." Digital version accessible at:, 1998. http://wwwlib.umi.com/cr/utexas/main.
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Reeves, Karyn. "Founder effects and related issues in Host-viral association studies." Thesis, Reeves, Karyn (2013) Founder effects and related issues in Host-viral association studies. PhD thesis, Murdoch University, 2013. https://researchrepository.murdoch.edu.au/id/eprint/16565/.
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Viruses such as HIV which replicate rapidly and with high transcription error rates may evade immune detection by mutating at key positions within the viral amino acid sequence. Large-scale host-viral association studies are conducted to identify positions of possible escape mutation in response to host immune pressure, with this pressure predominantly governed by genes within the human leukocyte antigen (HLA) complex. When transmission of the virus is HLA-associated, however, standard tests of association can be confounded by the relatedness of contemporarily circulating viral sequences, as sequences descended from a common ancestor may share inherited patterns of polymorphisms, termed „founder effects‟. A number of model-based methods utilizing inferred phylogenetic trees estimated from the observed viral sequences have been proposed to correct for this confounding, although such methods are typically computationally intensive and require specialist software for their implementation. In this thesis we propose an alternative empirical approach based on principal components analysis (PCA) which can be implemented using widely available software, and which adapts and extends methods currently used to control for population stratification in case-control genome-wide association studies. To accommodate data with small proportions commonly observed in host-viral studies we implement the PCA-based controlling procedure within a logistic regression framework using novel formulations motivated by the Frisch-Waugh-Lovell Theorem and demonstrate their utility in detecting true associations whilst minimizing confounding generated by founder effects via simulation. The approach is then extended to the multivariate setting through the adaptation of well-known techniques which expand the scope of host-viral analyses by accommodating possible linkages within the HLA and viral data.
The thesis concludes with a discussion of issues arising from the application of tail-based rejection regions and false discovery rates in large-scale analyses based on pooled contingency tables with varying margins. We argue that constraints imposed by the margins have implications overlooked in the rigid application of techniques developed for tests based on statistics with continuous distributions, but by leveraging the scale of such analyses it may be possible to consider local deviations between observed and expected p-value distributions to better identify hypotheses of interest.
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Bradley, Christopher James. "Molecular determinants of host susceptibility to meningococcal infection." Thesis, University of Bristol, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.289627.
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Stock, Emily. "Characterisation of host-range determinants in Chandipura virus." Thesis, University of Warwick, 2014. http://wrap.warwick.ac.uk/63027/.
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The emerging arbovirus, Chandipura virus (CHPV) has been implicated in epidemics of acute encephalitis in India with mortality rates in hospitalised children of over 50%. CHPV is a member of the Vesiculovirus genus of the Rhabdoviridae family. Viruses are dependent on the host cell at every stage of their lifecycle. The isolation of temperature-dependent host range (tdCE) mutants, which are characterised by growth impairment at 39°C in chick embryo (CE) cells but not in monkey cells, highlights a dependence of CHPV on undetermined host factors. The characterisation of three tdCE mutants was carried out. Each of the mutants contain one or more coding mutations in the RNA polymerase gene and two contain additional mutations in the attachment protein gene. Using a reverse genetics system of CHPV recombinant viruses containing the specific mutations were generated. This demonstrated that a single amino acid change in the virus RNA polymerase of each mutant, located either between domains III and IV or within domain IV or VI was responsible for host range specificity, the tdCE phenomenon. In CE cells at 39°C the tdCE lesions were shown to disrupt the assembly of cytoplasmic replication complexes. A recombinant virus with a Flag tag attached to the L protein was generated and used to infect mammalian and avian cells. Potential L/Flag interacting partners were co-immunoprecipitated and analysed by mass spectrometry. The predominant cellular functions of the identified proteins were in gene expression and the cytoskeleton. To investigate the neuropathogenisis and cell tropism of CHPV in vivo and ex vivo models of CHPV disease were established. The virus was shown to principally localise to the cerebellum in the mouse brain with the virus targeting immature neurons, granule cells and microglia. Mature neurons, oligodendrocytes and astrocytes were permissive to infection with CHPV but their infection occurred infrequently.
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Porter, Emily Louise. "Virus and host determinants of feline coronavirus pathogenicity." Thesis, University of Bristol, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.681565.
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Feline coronavirus (FCoV) infection is ubiquitous in multicat households in the UK. In the majority of cases, the infected cat remains healthy but a small percentage of cases develop the fatal disease of feline infectious peritonitis (FIP). This thesis describes the identification of genomic mutations that may account for the difference between the virulent and avirulent forms of FCoV. Complete FCoV genome sequences were obtained from two pairs of FCoV infected siblings, in which one of each pair died due to FIP whilst the other remained healthy. Virus-specific oligonucleotide primers were used to convert and amplify the FCo V genome RNA from each sample into cDNA fragments, which then underwent next generation sequencing. The de novo assembled genomes were compared and nucleotide differences between the genomes were identified. Thirty two nucleotide differences, which may be related to the development of FIP, were observed between the first pair of samples. The second pair of samples were found to represent only distantly related FCoV genomes. Recent evidence has suggested that one of the amino acid changes identified in this study, a methionine to leucine substitution at position 1058 in the spike protein may be associated with the development ofFIP. However, pyrosequencing analysis of a collection of well-defined clinical samples led to the conclusion that this amino acid change is linked to the tropism of the virus, rather than its ability to cause FIP. Finally, an initial step was taken towards exploring the host response to FCoV infection by comparing the levels of cellular transcripts between infected and mock infected feline cell lines. The experiments described in this thesis will help further our understanding of the roles played by the virus and the host in the pathogenesis of FCoV infections.
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Ke, Qi. "Negative Regulation of Host Innate Immune Signaling and Response Pathways by Viral and Host Regulatory Factors." University of Toledo / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1470185159.
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Bush, Victoria Louise. "The interaction of Neisseria meningitidis with host cells." Thesis, University of Nottingham, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.361473.
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Kreutzfeldt, Kaj Maximiliane. "Characterisation of host determinants that influence host-pathogen interaction during infection with Mycobacterium tuberculosis." Thesis, University of Brighton, 2015. https://research.brighton.ac.uk/en/studentTheses/9c2b2ddd-2ae7-4a8e-934a-a7e1dd28369a.
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Tuberculosis is endemic in the Gambian population, in which the magnitude of mycobacterial antigen-driven interferon-γ (IFN-γ) response in BCG vaccinated neonates has been linked to regions on the genome that encode the RIP2 kinase, the toll-like receptor 4 adapter protein MD-2 and the NF-κB subunit NF-κB2 by genome-wide linkage analysis. The receptor interacting protein (RIP2) is an essential kinase downstream of the nucleotide-binding oligomerization domain-containing protein 1 (NOD1) and NOD2, both intracellular pattern-recognition receptors for peptidoglycan moieties that induce activation of NF-κB. To establish the significance of RIP2 kinase during Mycobacterium tuberculosis infection, RIP2 was depleted in THP-1- derived macrophages using small interfering RNAs. In the absence of RIP2, THP- 1-derived macrophages secreted significantly reduced levels of the proinflammatory cytokine IL-1β upon infection with M. tuberculosis.
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Dalmau, Moreno Judith. "Viral and host factors involved in rapid HIV-1 disease progression." Doctoral thesis, Universitat Autònoma de Barcelona, 2014. http://hdl.handle.net/10803/133268.
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Els éssers humans mostren una notable variació en el desenvolupament clínic rere la infecció per VIH-1. Si bé algunes persones amb VIH-1 són capaces de suprimir la replicació viral del VIH a nivells molt baixos (<2000 còpies/ml) i/o mantenir els recomptes de CD4 alts durant molts anys en absència de teràpia antiretroviral (Controladors), altres progressen ràpidament a sida o compleixen els criteris actuals per a iniciar tractament antiretroviral en els 3 primers anys rere la infecció primària (Progressors ràpids, RP). D'altra banda, una minoria d'individus amb alts nivells de virèmia roman asimptomàtica i manté els recomptes de cèl·lules T CD4+ elevats (Virèmics no progressors, VNP), similars als observats en el model no progressiu d’infecció per SIV en l’hoste natural.
L'estudi de fenotips extrems pot donar informació rellevant en termes de les interaccions que s'estableixen entre el virus i l'hoste durant la infecció primària pel VIH, així com de l'evolució clínica posterior a la infecció. De fet, l'estudi dels controladors (incloent els controladors d’elit, que mantenen l’ARN viral a nivells indetectables) està proporcionant dades rellevants de la immunopatogènesi de la infecció. L'extrem oposat són els RPs, els quals representen un percentatge relativament petit de la població infectada per VIH-1. No obstant això, les implicacions de les seves característiques immunogenètiques i immunopatogèniques són notables .
Aquesta tesi té el seu origen en l’estudi exhaustiu de 2 casos de progressió extremadament severa i ràpida, que posteriorment es va estendre a la creació i l'estudi d'una cohort gran i ben definida de RPs sense precedents. L'objectiu específic va ser investigar una àmplia gamma de factors virals i de l'hoste implicats en la progressió ràpida de la infecció per VIH-1, en comparació amb altres fenotips, incloent individus amb un perfil estàndard de progressió (progressors estàndard, SP) i VNPs.
Els resultats d'aquest estudi demostren la convergència de factors virals i de l'hoste que contribueixen a la gravetat clínica de la progressió ràpida. Les persones infectades amb virus altament replicatius, dual-tròpics i HLA-adaptats van mostrar ser més propenses a desenvolupar símptomes definitoris de SIDA durant la infecció primària per VIH-1, donat que en molts casos tampoc no són capaces de produir respostes immunitàries humorals i cel·lulars específiques contra VIH-1. La concordança de supertipus d’HLA, la presència d'al·lels d’HLA comuns i d’al·lels de risc, i la baixa freqüència d’al·lels protectius, també van mostrar associació amb l’acceleració de la malaltia. A més, l'anàlisi del transcriptoma va revelar que els RPs tenen un perfil transcriptòmic específic a les cèl·lules T CD4+ i CD8+, similar a l'observat en la infecció patogènica per SIV en rhesus macacs, i caracteritzat per una major expressió de gens estimulats per l'interferó. Els VNPs, en canvi, es caracteritzen per un perfil de regulació de gens similar a la infecció no patogènica per SIV dels sooty mangabeys.
El present estudi proporciona informació rellevant sobre les característiques virals i de l’hoste implicades en la progressió ràpida de la infecció per VIH-1, la qual té implicacions destacables en el nostre coneixement de la patogènesi del VIH-1 i en la importància de la monitorització primerenca de l'evolució de la malaltia.<br>Remarkable variation in clinical outcome can be observed following HIV-1 infection. While some HIV-1–infected individuals are able to suppress viral replication to very low levels (<2000 copies/mL) and/or maintain high CD4+ T-cell counts over many years without antiretroviral therapy (HIV controllers), others quickly progress to AIDS or meet the current criteria for antiretroviral treatment within the first 3 years after primary infection (rapid progressors, RP). Furthermore, a minority of highly viremic individuals remain asymptomatic with high CD4+ T-cell counts (viremic non-progressors, VNP), similar to those observed in the non-progressive disease model of SIV infection in natural hosts.
The study of extreme phenotypes can provide important information on the interactions established between the viral variant and the host during primary HIV infection and the subsequent clinical evolution of the infection. Indeed, the study of HIV controllers (including elite controllers, who maintain plasma viral RNA under detectable levels [<50 copies/mL]) is providing relevant data on HIV immunopathogenesis. The other extreme comprises RPs, who account for a relatively small percentage of the HIV-1-infected population. Nevertheless, the implications of their immunogenetic and immunopathogenic characteristics are remarkable.
This thesis originates from the comprehensive study of 2 cases of extremely severe rapid progression that was later extended to the recruitment and study of an unprecedentedly large and well-defined cohort of RPs. The specific objective was to investigate a wide range of viral and host factors involved in rapid progression of HIV-1 infection, in contrast to other phenotypes, namely, individuals with an average progression profile (standard progressors, SP) and VNPs.
The results of this study demonstrate convergence of the viral and host factors contributing to the clinical severity of rapid progression. Individuals infected with highly replicative, dual-tropic, HLA-adapted viruses were shown to be more prone to develop AIDS-defining symptoms during primary HIV-1 infection, since in many cases they are also unable to mount humoral and cellular HIV-1-specific immune responses. Concordant HLA supertypes between the source and the recipient, the presence of common and risk HLA class I alleles, and the low frequency of protective HLA alleles were also shown to further accelerate disease progression. In addition, transcriptome analysis Revealed that RPs have a specific CD4+ and CD8+ T-cell transcriptome profile similar to that observed in pathogenic SIV-infected rhesus macaques and characterized by higher expression of interferon-stimulated genes. VNPs, on the other hand, were characterized by a gene regulation profile similar to that of non-pathogenic SIV-infected sooty mangabeys.
The present study provides important insights into the host and viral traits driving progression of HIV-1 infection, which have relevant implications for our knowledge of HIV pathogenesis and the importance of early monitoring of disease course.
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Khong, Anthony. "Characterization of cricket paralysis virus-host interaction and viral protein synthesis." Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/54692.
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Viruses are obligate parasites that have evolved strategies to recruit the translational machinery and inhibit antiviral defences. A relatively abundant family of positive-sense, monopartitate single stranded RNA viruses, dicistrovirus, remains relatively uncharacterized. Dicistroviruses are infectious to arthopods and have impacted a number of agricultural industries. Dicistroviruses, as indicated by their name, contain two open reading frames (ORFs). The 5'-untranslated internal ribosome entry site (5'-UTR IRES) directs translation of ORF1 which encodes non-structural proteins and the intergenic (IGR) IRES directs translation of ORF2 which encodes structural proteins. How dicistroviruses affect the host is not completely understood. My thesis focuses on several host pathways that are modulated during cricket paralysis virus (CrPV) infection, a model dicistrovirus. During CrPV infection, I discovered stress granule (SG) formation is inhibited but granules containing poly(A)+ mRNAs form. Furthermore, I discovered a viral protein, CrPV 1A, that inhibits the SG pathway. Upon further characterization of CrPV 1A, I discovered the viral protein also stimulates 5'-dependent translation and 5'IRES dependent translation. Finally, I found IGR IRES-dependent translation is delayed compared to 5'-UTR IRES-dependent translation, thus providing a viral strategy of expressing non-structural proteins such as the replicase and protease prior to the synthesis of structural proteins for viral packaging. This thesis provides insights into the key strategies of dicistrovirus infection, its viral life cycle and the innate immune responses in insect cells.<br>Medicine, Faculty of<br>Biochemistry and Molecular Biology, Department of<br>Graduate
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Delcorde, Julie. "Investigating Host-Viral Interactions in Liver Lipid Homeostasis and HCV Pathology." Thesis, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/31184.
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Hepatitis C virus (HCV) infects an estimated 170 million people worldwide and is a major cause of chronic hepatitis and hepatocellular carcinoma. As there are limited treatment options, the elucidation of novel host-viral interactions during HCV pathogenesis will be critical for the development of new therapeutics. My thesis work has identified cell death-inducing DFF45-like effector B (CIDEB) as a host factor that is disregulated during HCV infection, and has delineated the relevance of CIDEB’s dual roles in apoptosis and lipid metabolism in the context of the HCV lifecycle. Moreover, additional host factors necessary for the HCV lifecycle were investigated using unnatural amino acid (UAA) technology. With this technique, the photo-cross-linking UAA p-azido-phenlyalanine (AZF) and 3’-azibutyl-N-carbamoyl-lysine (Abk) were incorporated into viral proteins by expanding the genetic code of the host organism. This conferred diverse physicochemical and biological properties to these proteins that were exploited to investigate protein structure and function in vitro and in vivo. In summary, gaining insight into the numerous host-viral interactions that take place during HCV infection will both advance our understanding of HCV pathogenesis and uncover potential therapeutic targets.
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Cheng, Chi-Ping. "VIRAL RNA ELEMENTS AND HOST GENES AFFECTING RNA RECOMBINATION IN TOMBUSVIRUSES." UKnowledge, 2005. http://uknowledge.uky.edu/gradschool_diss/436.
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RNA recombination is a major factor driving viral evolution and contributing to new disease outbreaks. Therefore, understanding the mechanism of RNA recombination can help scientists to develop longer lasting antiviral strategies. Tombusviruses are one of the best model RNA viruses to study RNA virus recombination. My goals were to dissect the mechanism of tombusviral RNA recombination. To do so, in my thesis, I describe my results on the roles of (i) the viral replicase and the viral RNA templates; and (ii) the effect of host factors on tombusvirus recombination events. To study the mechanism of RNA recombination without the influence of selection pressure on the emerging recombinants, we developed an in vitro RNA recombination assay based on viral RNA templates and purified viral replicase preparations. Using this in vitro assay, we demonstrated that replicase driven template switching is the mechanism of recombination, whereas RNA ligation seems less likely to be a major mechanism. In addition, we also studied the role of RNA substrates, in more detail. Our results showed that viral replicase preferred to use functional RNA domains in the acceptor RNAs over random switching events. Host factors may also play important roles in RNA recombination. Using yeast as a model system for studying replication and recombination of a tombusvirus replicon, we identified 9 host genes affecting tombusvirus RNA recombination. Separate deletion of five of these genes enhanced generation of novel viral RNA recombinants. Further studies on one of these genes, XRN1, a 5-3 exoribonuclease, indicated that it might be involved in degradation of tombusvirus RNAs. Lack of Xrn1p resulted in accumulation of truncated (partially degraded) replicon RNAs, which became good templates for RNA recombination. To further study Xrn1p, we overexpressed Xrn4p of Arabidopsis thaliana, a functional analogue of the yeast Xrn1p, in Nicotiana benthamiana plants. After superinfecting the Xrn4p-overexpressing N. benthamiana with tombusvirus, truncated tombusvirus genomic and subgenomic RNA1 were observed. Some of the identified tombusvirus variants were infectious in protoplasts and could systemically infected N. benthamiana plants. Overall, this is the first report that a single host gene can affect rapid viral evolution and RNA recombination.
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Shair, Kathy Ho Yen. "Electromelia virus-host interactions : the viral growth factor and Schlafen proteins." Thesis, University of Cambridge, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.619967.
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Pore, Adam. "Studies on Host-Virus interaction for Viral Hemorrhagic Septicemia Virus (VHSv)." University of Toledo / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1336766667.
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Dos, Santos Filipa Miranda. "Exploring Viral Intra-Specific Variation and Behavior Through Host-Range Analysis." Thesis, The University of Arizona, 2014. http://hdl.handle.net/10150/555527.
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As the most abundant biological entity in the world’s oceans, marine viruses infect marine bacteria and contribute to major biogeochemical processes through their impacts on microbial metabolism. Despite decades of viral ecology studies, there is still much to learn about these viruses and their behavior. We examined 142 cyanophages isolated from two distinct ecological sites, 77 coastal and 65 upwelling. Phylogenomic analyses clustered these phages into 10 different phylogenetic species, with six of these species with at least three members and members originating from both the coastal and upwelling site. By testing these 142 cyanophages against 15 diverse Synechoccocus strains and analyzing the infectivity patterns associated with these interactions in the first large-scale quantitative host range (qHR), it is possible to explore the concepts of intra vs. inter specific variation and evaluate a potential viral bet hedging behavior. The qHR data has showed that there is more variation of host-range infectivity within species than between species and that viral bet hedging is indeed occurring as a way to minimize population-level extinction through the acceptance of a trade-off in maximal fitness for reduced temporal variance in fitness.
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Pascua, Laura del Carmen Lopez. "Environmental and genetic determinants of host-parasite coevolutionary dynamics." Thesis, University of Oxford, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.531978.
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Hanson, Paul J. "Viral protease disruption of host transcription and translation factors in the pathogenesis of coxsackievirus B3 induced viral myocarditis." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/57694.
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Myocarditis, inflammation of the heart muscle, is a spectrum of conditions causing significant morbidity and mortality, yet scientific and clinical knowledge related to this entity is limited. One of the most common and best studied causes of myocarditis is infection by coxsackievirus B3 (CVB3). An improved understanding of the science behind CVB3 myocarditis is critical to establishing better diagnostic and therapeutic strategies for affected individuals.
CVB3 infection redirects numerous cellular pathways from physiologic processes to viral replication, often mediated by viral proteases. Two viral targets in this process are death associated protein 5 (DAP5) and nuclear pore complex protein 98 (Nup98). DAP5 is a translation initiation factor specific to internal ribosome entry site (IRES) mediated translation. Nup98 is a component of the nuclear pore complex and a transcription factor.
In this thesis, I hypothesize that viral proteases contribute to the pathogenesis of viral myocarditis through interaction with DAP5 and Nup98, redirecting translation and transcription towards viral replication.
Using in vitro (plasmid expressed viral proteases), in situ (CVB3 infection in cell culture), and in vivo (mouse myocarditis model) models, I demonstrate that viral protease 2A is responsible for the cleavage of DAP5 and Nup98 during CVB3 infection. Both cleavage events I show to be integral to the viral lifecycle using over expression of recombinant fragments and siRNA inhibition of that expression.
These results suggest two previously unidentified targets for improved diagnostics and therapeutics for myocarditis, both areas for future research.<br>Medicine, Faculty of<br>Pathology and Laboratory Medicine, Department of<br>Graduate
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Bier, Katja. "Identification of viral and host factors involved in the assembly, processing and nuclear export of influenza A viral mRNPs." Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.534158.
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Ramaley, Patricia A. "Host genetics of HIV-1 infection and disease progression in Uganda." Thesis, University of Oxford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365714.
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Carlsson, Beatrice. "Human Caliciviruses: a study of viral evolution, host genetics and disease susceptibility." Doctoral thesis, Linköpings universitet, Molekylär virologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-76036.
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The viruses described in this thesis are the norovirus and sapoviruses, which belong to the family of human caliciviruses and are known to cause gastroenteritis in humans. Gastroenteritis has emerged as a global health problem and is based on the large number of infected considered as one of the most common diseases today. According to estimates of the World Health Organization (WHO), gastroenteritis causes over five times more pediatric deaths compared to pediatric deaths caused by HIV/AIDS worldwide. Norovirus, the cause of the famous “winter vomiting disease”, is alone responsible for more than 200 000 deaths each year in children less than 5 years of age. The mechanism for emergence and evolution of new human calicivirus strains, as well as protective immunity in the human population is poorly understood. The main focus for this thesis was to elucidate the possible correlation between human calicivirus evolution, host genetics and disease susceptibility. One of the main findings presented in this thesis is the documentation of in vivo capsid gene evolution and quasispecies dynamics during chronic NoV GI.3 infection (Paper 1). In paper II, we reported that the G428A nonsense mutation in the FUT2 gene provides strong but not absolute protection against symptomatic GII.4 NoV infection. In my last two papers (Paper III and IV), we were the first to investigate host genetic susceptibility factors during authentic SaV infection. To summarize, the results presented in this thesis show that the success of human calicivirus infection probably is determined by a delicate interplay between virus evolution and susceptibility of the host, both genetically and immunologically.
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Shapka, Natalia. "IDENTIFICATION OF VIRAL AND HOST FACTORS INVOLVED IN TOMBUSVIRUS REPLICATION AND RECOMBINATION." UKnowledge, 2006. http://uknowledge.uky.edu/gradschool_diss/449.
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Rapid evolution of RNA viruses with mRNA-sense genomes is a major concern to health and economic welfare due to the devastating diseases these viruses inflict on humans, animals and plants. Rapid viral RNA evolution is frequently due to RNA recombination, which can be facilitated by recombination signals present in viral RNAs. Among such signals are short sequences with high AU contents that constitute recombination hot spots in Brome mosaic virus (BMV) and retroviruses. We have demonstrated that a defective interfering (DI) RNA, a model template associated with Tomato bushy stunt virus (TBSV), a tombusvirus, undergoes frequent recombination in plants and protoplast cells when it carries the AU-rich hot spot sequence from BMV. Similar to the situation with BMV, most of the recombination junction sites in the DI RNA recombinants were found within the AU-rich region. Our results support the idea that common AU-rich recombination signals might promote interviral recombination between unrelated viruses. To test if host genes can affect the evolution of RNA viruses, we used a Saccharomyces cerevisiae single-gene deletion library, which includes ~80% of yeast genes, in RNA recombination studies based on a small viral replicon RNA derived from TBSV. The genome-wide screen led to the identification of five host genes, whose absence resulted in rapid generation of novel viral RNA recombinants. Thus, these genes normally suppress viral RNA recombination, but in their absence hosts become viral recombination hotbeds. Four of the five recombination suppressor genes are likely involved in RNA degradation, suggesting that RNA degradation could play a role in viral RNA recombination. Overall, our results demonstrate for the first time that a set of host genes have major effect on RNA virus recombination and evolution. Replication of the non-segmented, plus-stranded RNA genome of Cucumber necrosis tombusvirus (CNV) requires two essential overlapping viral-coded replication proteins, the p33 replication co-factor and the p92 RNA-dependent RNA polymerase. We have demonstrated that p33 is phosphorylated in vivo and in vitro by a membrane-bound plant kinase. Based on in vitro studies with purified recombinant p33, we show evidence for phosphorylation of threonine and serine residues adjacent to the essential RNA-binding site in p33. Our findings suggest that phosphorylation of threonine/serine residues adjacent to the essential RNA-binding site in the auxiliary p33 protein likely plays a role in viral RNA replication and subgenomic RNA synthesis during tombusvirus infections.
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Pathak, Kunj Bihari. "CHARACTERIZATION OF VIRAL AND HOST PROTEINS AND RNA ELEMENTS IN TOMBUSVIRUS REPLICATION." UKnowledge, 2011. http://uknowledge.uky.edu/plantpath_etds/1.
Full textAbstract:
Two thirds of plant viruses are positive-strand RNA viruses including the family Tombusviridae. One of the best-studied members of this family is Tomato bushy stunt virus (TBSV). Like many other viruses, TBSV has much fewer genes when compared to its hosts’ genome. Nevertheless, TBSV utilizes its genome very judiciously. To compensate for a lack of many proteins of its own, it codes for multi-functional replication protein p33 and also co-opts host factors to facilitate its replication.
By using recombinant replication proteins p33 and p92 containing single amino acid changes in protein-protein interaction domains (S1 and S2), I demonstrated that the replication proteins are required in sequential steps during virus replication. The in vitro cell-free extract(CFE) based TBSV replication assays revealed that mutations in S1 and S2 domains affected RNA template selection, recruitment and assembly of replicase complex. TBSV replicates on the cytosolic surface of peroxisomal membranes.
To identify the host factor involved in this process of transporting viral replication proteins to peroxisome, I tested the peroxisomal transporter proteins for their ability to bind to p33 in vitro, which led to the discovery of Pex19p. Pull-down and co-purification experiments revealed transient nature of p33-Pex19p binding as expected from a transporter. When pex19p was retargeted to mitochondria, a large fraction of p33 was also re-distributed to the mitochondria validating the importance of Pex19p in p33 localization.
TBSV also utilizes its genomic RNA for non-template activities during its replication. Accordingly, TBSV RNA serves as a platform for the assembly of replicase complex. To further characterize the regulatory cis-elements involved in this process, I utilized CFE and different TBSV RNA mutants together with recombinant p33 and p92 in vitro replication assays. These experiments revealed the role of RNA recruitment element [RIISL(+)] and 3’ non-coding regions as minimal cis-elements required to assemble functional replicase complex. The experiments also indicated that the RIISL(+) and 3’ non coding regions could be physically separated on two different RNA molecules to assemble TBSV replicase, suggesting insights into viral evolution.
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Lau, Sheung-Yee Kathy. "The trafficking of viral and host membrane proteins during HSV-1 assembly." Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708835.
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Pankajavally, Somanathan Pillai Smitha. "VIRAL AND HOST FACTORS AFFECTING INFECTION, PATHOGENICITY AND TRANSMISSION OF INFLUENZA VIRUSES." The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1250624574.
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Mehta, Roshni. "Viral and Host Factors Associated with HIV-1 Vertical Transmission and Pathogenesis." Diss., The University of Arizona, 2008. http://hdl.handle.net/10150/194040.
Full textAbstract:
The majority of neonates and infants acquire HIV-1 infection through vertical transmission. In addition these HIV-1 infected infants have a higher viral load and progress to AIDS faster than adults, often times more rapidly than their own infected mothers. However, the mechanisms of this differential disease progression are not well understood. Several studies have shown, including work from our laboratory, that it is the transmission of the minor genotype with the R5 phenotype that is involved in transmission. We have also shown that a lower viral heterogeneity may influence vertical transmission. Moreover, we have also shown that there is a differential HIV- influenced at the level of HIV-1 gene expression and not at the level of expression of receptors or coreceptors. Moreover, I have characterized the cellular gene expression profile of uninfected and infected cord monocyte-derived macrophages (MDM) as compared with adult MDMs. Evaluation of these cellular factors identified genes that fell into several classes including transcriptional activators/repressors, cytokines, and matrix metalloproteinases, all of which may be able to influence HIV-1 gene expression. To explain this differential HIV-1 gene expression, I have modulated the level of cellular factors (IL6 and STAT3) using short hairpin RNA (shRNA) technology to determine if these cellular factors were playing a role in an increased HIV-1 replication and gene expression. I found that upon downregulation of these factors, there was a decrease in HIV-1 LTR directed gene expression. Taken together, the results from this dissertation provide new insights into elucidating the mechanisms of HIV-1 vertical transmission and HIV-1 gene expression in neonates and infants. This work which has identified several cellular factors may offer new possibilities for the development of therapeutic strategies to treat pediatric AIDS.1 replication and HIV-1 gene expression in neonatal cells as compared to adult cells. The hypothesis of this dissertation is that viral determinants and cellular factors in neonatal and adult mononuclear cells influence HIV-1 replication and HIV-1 gene expression. In this dissertation I have molecularly characterized the HIV-1 long terminal repeat (LTR) from 6 mother-infant HIV-1 infected pairs, and shown that mutations generated during vertical transmission correlate with HIV-1 gene expression. Furthermore, I have also shown that there was a low degree of viral heterogeneity and a high conservation of critical transcription factor binding sites within the LTR. I have also shown that nuclear extracts from neonatal (cord) mononuclear cells bind with higher efficiencies to HIV-1 LTR as compared to nuclear extracts from adult mononuclear cells. In addition, I have also made strides in trying to elucidate the mechanisms of differential HIV-1 replication and gene expression. I have shown that there is a differential HIV-1 replication in naïve and memory T-lymphocytes from cord vs. adults and this increased HIV-1 replication was
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Beckham, Carla Jolene. "Analysis of Connections Between Host Cytoplasmic Processing Bodies and Viral Life Cycles." Diss., The University of Arizona, 2007. http://hdl.handle.net/10150/194209.
Full textAbstract:
In the past few years, cytoplasmic processing bodies (P-Bodies) have been identified in eukaryotic cells. P-bodies have roles in translational repression, mRNA storage, mRNA decay and are conserved cytoplasmic aggregations of non-translating mRNAs in conjunction with translation repression and mRNA degradation factors. In this work, I, in collaboration with others provide evidence for a new biological role for P-bodies in viral life cycles. This work can be summarized thus:In a collaborative effort, I have identified connections between retrovirallike transposon life cycles and P-bodies. For example, genetic evidence in yeast indicates that key proteins within P-bodies are required for the life cycles of the Ty1 and Ty3 retrotransposons. Moreover, Ty3 genomic RNA (gRNA) as well as viral structural proteins accumulate in P-bodies, suggesting that P-bodies may serve as sites of viral assembly.Second, I have shown, with assistance of collaborators, that the positivestrand RNA virus, Brome Mosaic Virus (BMV) gRNA accumulates in P-bodies Moreover, viral RNA dependent RNA polymerase (RdRp) colocalizes with and co-immunoprecipitates with the P-body protein Lsm1p, suggesting that P-bodies may participate in viral replication. Remarkably, the accumulation BMV gRNA in P-bodies is dependent on cis-elements that have been demonstrated to play critical roles in viral RNA replication.The identification of P-bodies as sites of accumulation of viral gRNA and viral proteins of both retro-virus like elements and positive-stranded RNA viruses, expands the list of important biological roles played by P-bodies. Since P-body proteins and structure are highly conserved, these findings imply that Pbodies will be important for other RNA viruses.