Cellular Entry of Lymphocytic Choriomeningitis Virus

Rojek, Jillian M.; Perez, Mar; Kunz, Stefan

doi:10.1128/jvi.01331-07

Cited by 93 publications

(111 citation statements)

References 79 publications

(116 reference statements)

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“…Recombinant wild-type LCMV (rLCMV/WT) and rLCM viruses expressing vesicular stomatitis virus G (rLCMV/VSV-G), or LASV GPC (rLCMV/LASV-GPC), instead of LCMV GPC, as well as the recombinant WT VSV (VSV/WT) and rVSV expressing GPC of LCMV instead of VSV G (rVSV/LCMV-GPC), has been previously described (17,21,23,24,28). To generate rLCMV GFP-P2A-NP, we replace the NP open reading frame (ORF) in plasmid moPol-I/Sag (17,21) by the ORF GFP-P2A-NP that contained the ORF of GFP tagged to the N terminus of NP, separated by the 2A peptide sequence derived from porcine teschovirus (PVT1: P2A) (27).…”

Section: Methodsmentioning

confidence: 99%

Identification and Mechanism of Action of a Novel Small-Molecule Inhibitor of Arenavirus Multiplication

Ngo

Cubitt

Iwasaki

et al. 2015

J Virol

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Several arenaviruses cause hemorrhagic fever disease in humans and represent important public health problems in the regions where these viruses are endemic. In addition, evidence indicates that the worldwide-distributed prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is an important neglected human pathogen. There are no licensed arenavirus vaccines and current antiarenavirus therapy is limited to the use of ribavirin that is only partially effective. Therefore, there is an unmet need for novel antiarenaviral therapeutics. Here, we report the generation of a novel recombinant LCM virus and its use to develop a cell-based high-throughput screen to rapidly identify inhibitors of LCMV multiplication. We used this novel assay to screen a library of 30,400 small molecules and identified compound F3406 ( A renaviruses are enveloped viruses with a bisegmented negative-strand RNA genome. Each genome segment, large (L; ϳ7.3 kb) and small (S; ϳ3.5 kb) uses an ambisense coding strategy to direct synthesis of two polypeptides in opposite direction, separated by a noncoding intergenic region (IGR) (1, 2). The S segment encodes for the viral nucleoprotein (NP) and the glycoprotein precursor (GPC), which is co-and posttranslationally processed by the signal peptidase and SKI-1/S1P cellular proteases, respectively, to produce the mature surface virion glycoproteins GP1 and GP2 and the stable signal peptide (SSP) that together form the GP1/GP2/SSP complex present at the surface of mature virions and that mediate receptor recognition and cell entry (1, 3). The L segment encodes the viral RNA-dependent RNA polymerase (L polymerase) and the matrix Z protein. Arenaviruses cause chronic infections of rodents with worldwide distribution, where human infections occur through mucosal exposure to aerosols or by direct contact of abraded skin with infectious material. Several arenaviruses cause hemorrhagic fever (HF) disease in humans and pose important public health problems in regions where these viruses are endemic (1, 4-8). Thus, Lassa virus (LASV) infects several hundred thousand people yearly in West Africa, resulting in a high number of Lassa fever cases that are associated with high morbidity and mortality. Likewise, Junin virus (JUNV) causes Argentine HF, a severe illness endemic to Pampas in Argentina, which is characterized by hemorrhagic and neurological manifestations and a fatality rate of 15 to 30% (8). Moreover, mounting evidence indicates that the worldwide-distributed prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is a neglected human pathogen of clinical significance (9-12). In addition, several arenaviruses, including LASV, JUNV, and LCMV, pose a credible biodefense threat (13). Concerns about arenavirus infections of humans are exacerbated due to the lack of U.S. Food and Drug Administrationlicensed vaccines and current antiarenaviral therapy being limited to an off-label use of ribavirin (Rib) that is only partially effective (14-16). Therefore, there is an unmet need to iden...

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Section: Methodsmentioning

confidence: 99%

Identification and Mechanism of Action of a Novel Small-Molecule Inhibitor of Arenavirus Multiplication

Ngo

Cubitt

Iwasaki

et al. 2015

J Virol

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“…Previous reports suggest that these lipid microdomains can act as scaffolds or platforms for protein-protein interactions and protein compartmentalization (70,71). Similar to our observations with VSV-G pseudotyped vectors, several reports suggest that endocytic routes of viral entry into target cells are dependent on cellular cholesterol but are independent of flotillin-1/Reggie-2, caveolin-1, or clathrin (72,73). Thus, lipid microdomains may provide subcellular microenvironments where antiviral factors, such as TRIM5␣, Lv2, and CD317/BST-2/tetherin, can recognize and/or sense viral components.…”

Section: Discussionsupporting

confidence: 88%

Cytoplasmic Body Component TRIM5α Requires Lipid-enriched Microdomains for Efficient HIV-1 Restriction

Ohmine

Sakuma

et al. 2010

Journal of Biological Chemistry

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TRIM5␣ is a member of the tripartite motif (TRIM) family of proteins and affects both early and late phases of the retroviral life cycle. Although TRIM5␣ multimerizes to form cytoplasmic bodies, which are thought to play an important role in viral restriction, the identity of TRIM5␣-containing cytoplasmic bodies remains elusive. To better understand TRIM5␣ cytoplasmic body constituents and the cellular proteins that could be involved in the TRIM5␣-mediated antiviral activities, we sought TRIM5␣-binding factors. We identified a lipid microdomain protein flotillin-1/Reggie-2 as an interacting partner of TRIM5␣ via co-immunoprecipitation. Immunohistochemistry studies confirmed the co-localization of rhesus monkey TRIM5␣ (TRIM5␣rh) cytoplasmic bodies with flotillin-1/Reggie-2. Caveolin-1, another lipid microdomain-associated protein, also co-localized with TRIM5␣ cytoplasmic bodies. Intriguingly, disruption of cellular cholesterol by cyclodextrin perturbed TRIM5␣ cytoplasmic body formation. Furthermore, lipid starvation partially relieved the endogenous post-entry restriction of HIV-1 infection, which could be subsequently restored by lipid repletion. These observations indicate the involvement of cellular lipids in TRIM5␣-mediated antiviral activities. Given that many viruses utilize cellular lipid microdomains for viral entry and assembly, it is plausible that lipid-enriched domains provide microenvironments where TRIM5␣ recognizes retroviral components.

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“…For this, we transfected Ol cells with GFP-tagged versions of WT and DN forms of Eps15 and at 24 h posttransfection infected them with BDV (MOI ϭ 0.1). As controls, Ol-transfected cells were also infected with VSV, whose cell entry is clathrin dependent (60) or LCMV, which uses a clathrin-and caveola-independent pathway for cell entry (48,51). The use of GFP-tagged versions of WT and DN Eps15 proteins allowed us to correlate the expression of these proteins with virus infection at the singlecell level.…”

Section: Resultsmentioning

confidence: 99%

“…To assess the possible contribution of caveolar endocytosis to BDV cell entry, we used a DN mutant of caveolin-1 (CAV1 Y14F), which has been shown to prevent caveola-mediated cell entry of other viruses (51). We transfected Ol cells with GFPtagged versions of WT and DN CAV1 and subsequently infected them with BDV (MOI ϭ 0.1).…”

Section: Resultsmentioning

confidence: 99%

Cell Entry of Borna Disease Virus Follows a Clathrin-Mediated Endocytosis Pathway That Requires Rab5 and Microtubules

Clemente

Torre

2009

J Virol

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Borna disease virus (BDV), the prototypic member of the Bornaviridae family within the order Mononegavirales, exhibits high neurotropism and provides an important and unique experimental model system for studying virus-cell interactions within the central nervous system. BDV surface glycoprotein (G) plays a critical role in virus cell entry via receptor-mediated endocytosis, and therefore, G is a critical determinant of virus tissue and cell tropism. However, the specific cell pathways involved in BDV cell entry have not been determined. Here, we provide evidence that BDV uses a clathrin-mediated, caveola-independent cell entry pathway. We also show that BDV G-mediated fusion takes place at an optimal pH of 6.0 to 6.2, corresponding to an early-endosome compartment. Consistent with this finding, BDV cell entry was Rab5 dependent but Rab7 independent and exhibited rapid fusion kinetics. Our results also uncovered a key role for microtubules in BDV cell entry, whereas the integrity and dynamics of actin cytoskeleton were not required for efficient cell entry of BDV.

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Cellular Entry of Lymphocytic Choriomeningitis Virus

Cited by 93 publications

References 79 publications

Identification and Mechanism of Action of a Novel Small-Molecule Inhibitor of Arenavirus Multiplication

Identification and Mechanism of Action of a Novel Small-Molecule Inhibitor of Arenavirus Multiplication

Cytoplasmic Body Component TRIM5α Requires Lipid-enriched Microdomains for Efficient HIV-1 Restriction

Cell Entry of Borna Disease Virus Follows a Clathrin-Mediated Endocytosis Pathway That Requires Rab5 and Microtubules

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