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Search Results: 1 - 10 of 322299 matches for " Thomas J. Hope "
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Full-length Ebola glycoprotein accumulates in the endoplasmic reticulum
Suchita Bhattacharyya, Thomas J Hope
Virology Journal , 2011, DOI: 10.1186/1743-422x-8-11
Abstract: Ebola GP is the only viral protein expressed on the virus surface and mediates entry into target cells [1], [2]. However, several studies report that GP expression also causes cell rounding and cytotoxicity, although the underlying mechanism remains unknown. For instance, expression of Ebola GP but not Marburg GP is reported to cause cell detachment without death [3]. Additionally, Ebola GP from Zaire, Sudan and Ivory Coast subtypes are shown to cause cell rounding and detachment ascribed to down-regulation of MHC class I and cell surface adhesion proteins [4], [5]. Interestingly, Ebola GP from the Reston subtype, believed to be non-pathogenic to humans, had a less severe cell rounding effect [4]. GP is also believed to be a key determinant of viral pathogenesis and virus-like particles (VLPs) containing GP are shown to activate human endothelial cells and macrophages [6], [7]. Importantly, the mucin-like region in GP1 is specifically shown to induce cytotoxicity when GP is expressed at similar levels to that seen during Ebola virus infection. Additionally, the other virus proteins tested were not cytotoxic [8]. Collectively, these reports indicate that Ebola GP imparts cell rounding and cytotoxicity in addition to facilitating viral entry.However, separate work reports that Ebola Zaire GP is not cytotoxic when expressed in isolation at similar levels to that seen during early virus infection [9]. Another study shows that GP is not detected in cells infected with Ebola Zaire virus [10]. This failure to detect GP during infection may arise as GP is released from the infected cells either as soluble glycoprotein (sGP) or a soluble form of GP1 [11]. As full-length GP but not sGP is shown to cause cytotoxicity [12], this suggests that the release of sGP during Ebola virus infection could be a mechanism used by the virus to prevent cytotoxicity and replicate and spread throughout the body. Moreover, this release of sGP may also explain why Ebola Zaire GP expressed at lev
Cellular Factors Implicated in Filovirus Entry
Suchita Bhattacharyya,Thomas J. Hope
Advances in Virology , 2013, DOI: 10.1155/2013/487585
Cellular Factors Implicated in Filovirus Entry
Suchita Bhattacharyya,Thomas J. Hope
Advances in Virology , 2013, DOI: 10.1155/2013/487585
Abstract: Although filoviral infections are still occurring in different parts of the world, there are no effective preventive or treatment strategies currently available against them. Not only do filoviruses cause a deadly infection, but they also have the potential of being used as biological weapons. This makes it imperative to comprehensively study these viruses in order to devise effective strategies to prevent the occurrence of these infections. Entry is the foremost step in the filoviral replication cycle and different studies have reported the involvement of a myriad of cellular factors including plasma membrane components, cytoskeletal proteins, endosomal components, and cytosolic factors in this process. Signaling molecules such as the TAM family of receptor tyrosine kinases comprising of Tyro3, Axl, and Mer have also been implicated as putative entry factors. Additionally, filoviruses are suggested to bind to a common receptor and recent studies have proposed T-cell immunoglobulin and mucin domain 1 (TIM-1) and Niemann-Pick C1 (NPC1) as potential receptor candidates. This paper summarizes the existing literature on filoviral entry with a special focus on cellular factors involved in this process and also highlights some fundamental questions. Future research aimed at answering these questions could be very useful in designing novel antiviral therapeutics. 1. Introduction The Filoviridae family comprises of three genera: Ebolavirus, Marburgvirus, and Cuevavirus (tentative). These enveloped viruses are nonsegmented with negative-sense RNA and produce filamentous virions, which are pleomorphic in shape [1]. Ebolavirus has five known species: Zaire (EBOV), Sudan (SUDV), Reston (RESTV), Tai Forest (TAFV), and Bundibugyo (BDBV) while Marburgvirus has only one species: Marburg virus (MARV) [2–9]. EBOV and MARV and are known to be serologically, biochemically, and genetically distinct [10, 11]. The filoviral genome encodes seven structural proteins: envelope glycoprotein (GP), major matrix protein (VP40), nucleoprotein (NP), polymerase cofactor (VP35), replication/transcription protein (VP30), minor matrix protein (VP24), and RNA dependent DNA polymerase (L). In addition to this, EBOV also expresses a small, secreted, nonstructural glycoprotein (sGP) (see [12] for a comprehensive review). Filoviruses are transmitted through contact with infected blood or body fluids [13] and can infect many cell types across different host species with lymphocytes being the notable exception [14, 15]. Although filoviruses are known to be pantropic, their preferred target cells
The temperature arrested intermediate of virus-cell fusion is a functional step in HIV infection
Hamani I Henderson, Thomas J Hope
Virology Journal , 2006, DOI: 10.1186/1743-422x-3-36
Abstract: The fusion process of HIV envelope (Env) is a highly concerted and cooperative process between viral particles and human target cells. HIV Env mediated fusion is initiated through gp120 interactions with cell surface CD4 [1]. These interactions lead to conformational changes in Env, which expose binding sites to the principle cellular coreceptors CCR5 or CXCR4 [2]. CD4 binding also induces conformational changes in the gp41 subunit of Env, leading to exposure of the N-terminal hydrophobic fusion peptide and the heptad repeats [1]. The fusion peptide then inserts into the host cell plasma membrane, which brings the two membranes together to allow fusion. Recently, much attention has focused on events related to the fusion of viral and target cell membranes. These studies have provided insight into intermediate stages within the fusion process, which has led to the development of successful alternative drug therapies. For example, enfuvirtide (T-20) was recently approved for clinical treatment of HIV-1. T-20 is a peptide fusion inhibitor, which disrupts fusion by interacting with the N-terminal helical regions within gp41 to prevent six-helix bundle formation. Although enfuvirtide and other entry inhibitors utilize unique mechanisms to disrupt HIV entry, the virus can readily develop resistance to these compounds. Therefore, much remains to be elucidated regarding the kinetics and rate-limiting steps involved in viral fusion.Much of the analysis of HIV fusion has been in the context of cell-cell based fusion assays. Typically, effector cells that express fusion proteins on their surface are coincubated with target cells expressing the appropriate receptor and coreceptors. Fusion between effector and target cells is measured by lipid or cytoplasmic content mixing [3]. Although these assays provide valuable information regarding fusion, it is important to fully assess all the variables governing fusion of virions to their cellular targets because of differences between
CCR5 Conformations Are Dynamic and Modulated by Localization, Trafficking and G Protein Association
Ayanna J. Flegler, Gianguido C. Cianci, Thomas J. Hope
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0089056
Abstract: CCR5 acts as the principal coreceptor during HIV-1 transmission and early stages of infection. Efficient HIV-1 entry requires a series of processes, many dependent on the conformational state of both viral envelope protein and cellular receptor. Monoclonal antibodies (MAbs) are able to identify different CCR5 conformations, allowing for their use as probes to distinguish CCR5 populations. Not all CCR5 MAbs are able to reduce HIV-1 infection, suggesting the use of select CCR5 populations for entry. In the U87.CD4.CCR5-GFP cell line, we used such HIV-1-restricting MAbs to probe the relation between localization, trafficking and G protein association for individual CCR5 conformations. We find that CCR5 conformations not only exhibit different localization and abundance patterns throughout the cell, but that they also display distinct sensitivities to endocytosis inhibition. Using chemokine analogs that vary in their HIV-1 inhibitory mechanisms, we also illustrate that responses to ligand engagement are conformation-specific. Additionally, we provide supporting evidence for the select sensitivity of conformations to G protein association. Characterizing the link between the function and dynamics of CCR5 populations has implications for understanding their selective targeting by HIV-1 and for the development of inhibitors that will block CCR5 utilization by the virus.
Evidence for Direct Involvement of the Capsid Protein in HIV Infection of Nondividing Cells
Masahiro Yamashita,Omar Perez,Thomas J Hope,Michael Emerman
PLOS Pathogens , 2007, DOI: 10.1371/journal.ppat.0030156
Abstract: HIV and other lentiviruses can productively infect nondividing cells, whereas most other retroviruses, such as murine leukemia virus, require cell division for efficient infection. However, the determinants for this phenotype have been controversial. Here, we show that HIV-1 capsid (CA) is involved in facilitating HIV infection of nondividing cells because amino acid changes on CA severely disrupt the cell-cycle independence of HIV. One mutant in the N-terminal domain of CA in particular has lost the cell-cycle independence in all cells tested, including primary macrophages. The defect in this mutant appears to be at a stage past nuclear entry. We also find that the loss of cell-cycle independence can be cell-type specific, which suggests that a cellular factor affects the ability of HIV to infect nondividing cells. Our data suggest that CA is directly involved at some step in the viral life cycle that is important for infection of nondividing cells.
Review of the twelfth West Coast retrovirus meeting
Sheila M Barry, Marta Melar, Philippe Gallay, Thomas J Hope
Retrovirology , 2005, DOI: 10.1186/1742-4690-2-72
Abstract: John Young of the Salk Institute began this session by describing work his lab has recently completed in understanding cellular requirements for replication of Murine Leukemia Virus (MLV) [1]. Through use of chemically mutagenized CHO cells, they identified five clones that became resistant to MLV infection. Additional studies revealed this restriction was specific to the MLV core. After confirming the virus was blocked prior to integration, the clones were separated into two phenotypes, those which blocked reverse transcription early and those which allowed reverse transcription and nuclear entry, but prevented viral integration. Young and colleagues are currently identifying cellular factors involved in the latter phenotype. While the exact identities of these cellular factors were not revealed, Young shared that they believe one is an enzyme and the other a putative transcription factor.Pankaj Kumar from Lorraine Albritton's lab at the University of Tennessee continued this theme by examining cellular factors involved in Moloney MLV entry. Previous work found that the exposure of MLV to proteases enhanced the viral infectivity and certain cell lines, including XC cells, innately possessed proteases that could facilitate MLV infection. The group decided to focus on cathepsins, since expression of these cellular proteases is induced under these conditions. They found a broad spectrum cathepsin inhibitor as well as a cathepsin B-specific inhibitor reduced Moloney MLV infectivity. Additionally, treatment of viral particles with cathepsin B resulted in cleavage of the surface glycoprotein (SU). They postulate Moloney MLV encounters cathepsin B within early lysosomes and the ensuing cleavage of SU facilitates fusion and entry steps.Two talks turned attention to the involvement of HIV envelope glycoprotein gp41 in early steps of viral infection. In work previously published by his lab, John Day of the University of California San Diego and others determined the membrane
Differential Binding of IgG and IgA to Mucus of the Female Reproductive Tract
Kelly M. Fahrbach, Olga Malykhina, Daniel J. Stieh, Thomas J. Hope
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0076176
Abstract: Cells of the endocervix are responsible for the secretion of mucins, which provide an additional layer of protection to the female reproductive tract (FRT). This barrier is likely fortified with IgA as has previously been shown in the gastrointestinal tract and lungs of mice. Mucus associated IgA can facilitate clearance of bacteria. While a similar function for IgG has been proposed, an association with mucus has not yet been demonstrated. Here we find that IgA and IgG are differentially associated with the different types of mucus of the FRT. We observed that while both IgA and IgG are stably associated with cervical mucus, only IgG is associated with cervicovaginal mucus. These findings reveal that antibodies can bind tightly to mucus, where they can play a significant role in the fortification of the mucus barriers of the FRT. It may be possible to harness this interaction in the development of vaccines designed to protect the FRT mucosal barriers from sexually transmitted diseases such as HIV.
Lymphatic filariasis in the Democratic Republic of Congo; micro-stratification overlap mapping (MOM) as a prerequisite for control and surveillance
Louise A Kelly-Hope, Brent C Thomas, Moses J Bockarie, David H Molyneux
Parasites & Vectors , 2011, DOI: 10.1186/1756-3305-4-178
Abstract: We analysed maps of onchocerciasis community-directed treatment with ivermectin (CDTi) from the African Programme for Onchocerciasis Control (APOC); maps of predicted prevalence of Loa loa; planned STH control maps of albendazole (and mebendazole) from the Global Atlas of Helminth Infections (GAHI); and bed nets and insecticide treated nets (ITNs) distribution from Demographic and Health Surveys (DHS) as well as published historic data which were incorporated into overlay maps. We developed an approach we designate as micro-stratification overlap mapping (MOM) to identify areas that will assist the implementation of LF elimination in the DRC. The historic data on LF was found through an extensive review of the literature as no recently published information was available.This paper identifies an approach that takes account of the various factors that will influence not only country strategies, but suggests that country plans will require a finer resolution mapping than usual, before implementation of LF activities can be efficiently deployed. This is because 1) distribution of ivermectin through APOC projects will already have had an impact of LF intensity and prevalence 2) DRC has been up scaling bed net distribution which will impact over time on transmission of W. bancrofti and 3) recently available predictive maps of L. loa allow higher risk areas to be identified, which allow LF implementation to be initiated with reduced risk where L. loa is considered non-endemic. We believe that using the proposed MOM approach is essential for planning the expanded distribution of drugs for LF programmes in countries co-endemic for filarial infections.The Democratic Republic of Congo (DRC) is the largest lymphatic filariasis (LF) endemic country in Africa with over 49 million people at risk [1-3]. The challenge of mapping LF in the 2.3 m sq km of inhabited regions is further compounded by co-endemicity with Loa loa and the poor road infrastructure in the post-conflict enviro
Trafficking of some old world primate TRIM5α proteins through the nucleus
Felipe Diaz-Griffero, Daniel E Gallo, Thomas J Hope, Joseph Sodroski
Retrovirology , 2011, DOI: 10.1186/1742-4690-8-38
Abstract: Here we report that the TRIM5α proteins of two Old World primates, humans and rhesus monkeys, are transported into the nucleus and are shuttled back to the cytoplasm by a leptomycin B-sensitive mechanism. In leptomycin B-treated cells, these TRIM5α proteins formed nuclear bodies that also contained TRIM19 (PML). Deletion of the amino terminus, including the linker 1 (L1) region, resulted in TRIM5α proteins that accumulated in nuclear bodies. Leptomycin B treatment of TRIM5α-expressing target cells only minimally affected the restriction of retrovirus infection.We discovered the ability of human and rhesus TRIM5α to shuttle into and out of the nucleus. This novel trafficking ability of TRIM5α proteins could be important for an as-yet-unknown function of TRIM5α.Proteins of the tripartite motif (TRIM) family contain RING, B-Box and coiled-coil domains, and thus have been referred to as RBCC proteins [1]. Members of this family have been implicated in diverse processes such as cell proliferation, differentiation, development, oncogenesis and apoptosis [1,2]. TRIM proteins often self-associate and, when overexpressed, aggregate to form nuclear or cytoplasmic bodies [1].TRIM5α is a cytoplasmic protein that is capable of restricting retrovirus infection in a species-dependent manner [3]. Variation among TRIM5α proteins in different primates accounts for the early, post-entry blocks to infection by particular retroviruses [3-7]. For example, TRIM5α proteins of Old World monkeys block human immunodeficiency virus (HIV-1) infection [3-5,7], whereas TRIM5α proteins of New World monkeys block infection by simian immunodeficiency virus (SIVmac) [8]. TRIM5α from humans (TRIM5αhu) is not as potent in restricting HIV-1 infection as Old World monkey TRIM5α, but TRIM5αhu potently restricts other retroviruses, e.g., N-tropic murine leukemia virus (N-MLV) and equine infectious anemia virus (EIAV) [3,4,6-8]. Owl monkeys, a New World monkey species, are unusual in not expressing a TRIM5α
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