Neurovirulent Virus Research Articles

A substitution in nsP1 combined with a double substitution in E2 glycoprotein renders Sindbis-like virus XJ-160 fully neurovirulent for adult mice

Sindbis virus (SV) can be rendered neurovirulent for adult mice by a double substitution within the E2 glycoprotein, including replacing Gln at position 55 of E2 with a His (E2-55: Gln–His) and E2-70: Glu to Lys. However, the mutant Sindbis-like virus XJ-160 with the double substitution (BR-E5570) does not show neurovirulence for adult mice, although the mutant apparently reduced the average survival time of neonatal mice. To produce an XJ-160 virus neurovirulent for adult mice, the BR-E5570 virus containing the double substitution was provided with another substitution in the nsP1 region (nsP1-173: Thr–Ile), which could enhance viral infectivity and neurovirulence for neonatal mice. The mutant containing these three substitutions was accordingly designated as BR-5570-ns173. Like the BR-XJ160 virus derived from the wild-type clone, BR-E5570 and BR-E5570-ns173 were both virulent for newborn mice, between which BR-E5570-ns173 virus showed the greatest neurovirulence. Furthermore, only BR-E5570-ns173 virus was fully neurovirulent for 14-day-old mice, and this fatal adult mouse-virulence was dependent on the E2 double substitutions at positions 55 and 70. Compared with BR-XJ160, both the mutants showed a higher capacity for propagation both in cultured cells and in the mouse brain. In particular, BR-E5570-ns173 virus showed a more persistent existence and higher titer in the brains of 7-day-old mice. These findings indicate that the substitution at nsP1-173 combination with a double substitution in the E2 region renders the XJ-160 virus fully neurovirulent for adult mice, and this neurovirulence may be related to the increased efficiency and persistence of propagation of this virus.

Longitudinal cerebral metabolic changes in pig-tailed macaques infected with the neurovirulent virus SIVsmmFGb.

Longitudinal cerebral metabolite changes in pig-tailed macaques inoculated with the simian immunodeficiency virus SIVsmmFGb were evaluated with in vivo proton MRS at 3 T. Blood sample collection, and MRS were carried out before and 2, 4, 8, 12, 16, 20, and 24 weeks after SIV inoculation. Significant reduction of N-acetylaspartate (NAA)/creatine (Cr) and choline (Cho)/Cr ratios in prefrontal gray matter (PGM) and glutamate/glutamine(Glx)/Cr ratio in striatum, and increase of myo-inositol (mI)/Cr in striatum were observed during acute SIV infection. The metabolite alterations during the SIVsmmFGb infection are largely in agreement with previous findings in other non-human primate models and HIV patients. Also, NAA/Cr in PGM and striatum and Glx/Cr in striatum are negatively correlated with the percentage of CD8+ T cells after the SIV infection, suggesting the interaction between brain metabolite and immune dysfunction. The present study complements previous studies by describing the time course of alterations of brain metabolites during SIVsmmFGb infection. The findings further demonstrate the efficacy of the SIVsmmFGb-infected macaque as a model to characterize central nervous system infection using novel neuroimaging approaches and also as a tool for exploration of novel and advanced neuroimaging techniques in HIV/AIDS studies.

Manipulation of host factors optimizes the pathogenesis of western equine encephalitis virus infections in mice for antiviral drug development.

While alphaviruses spread naturally via mosquito vectors, some can also be transmitted as aerosols making them potential bioterrorism agents. One such pathogen, western equine encephalitis virus (WEEV), causes fatal human encephalitis via multiple routes of infection and thus presumably via multiple mechanisms. Although WEEV also produces acute encephalitis in non-human primates, a small animal model that recapitulates features of human disease would be useful for both pathogenesis studies and to evaluate candidate antiviral therapies. We have optimized conditions to infect mice with a low passage isolate of WEEV, thereby allowing detailed investigation of virus tropism, replication, neuroinvasion, and neurovirulence. We find that host factors strongly influence disease outcome, and in particular, that age, gender, and genetic background all have significant effects on disease susceptibility independent of virus tropism or replication within the central nervous system. Our data show that experimental variables can be adjusted in mice to recapitulate disease features known to occur in both non-human primates and humans, thus aiding further study of WEEV pathogenesis and providing a realistic therapeutic window for antiviral drug delivery.

Phosphorylation of herpes simplex virus 1 dUTPase regulates viral virulence and genome integrity by compensating for low cellular dUTPase activity in the central nervous system.

A mutation in herpes simplex virus 1 dUTPase (vdUTPase), which precluded its phosphorylation at Ser-187, decreased viral neurovirulence and increased mutation frequency in progeny virus genomes in the brains of mice where endogenous cellular dUTPase activity was relatively low, and overexpression of cellular dUTPase restored viral neurovirulence and mutation frequency altered by the mutation. Thus, phosphorylation of vdUTPase appeared to regulate viral virulence and genome integrity by compensating for low cellular dUTPase activity in vivo. Many DNA viruses encode a homolog of host cell dUTPases, which are known to function in accurate replication of cellular DNA genomes. The viral dUTPase activity has long been assumed to play a role in viral replication by preventing mutations in progeny virus genomes if cellular dUTPase activity was not sufficient. Here, we showed that a mutation in herpes simplex virus 1 dUTPase, which precluded its phosphorylation at Ser-187 and reduced its activity, decreased viral neurovirulence and increased mutation frequency in progeny virus genomes in the brains of mice where endogenous cellular dUTPase activity was relatively low. In contrast, overexpression of cellular dUTPase restored viral neurovirulence and mutation frequency altered by the mutation in the brains of mice. This is the first report, to our knowledge, directly showing that viral dUTPase activity regulates viral genome integrity and pathogenicity by compensating for insufficient cellular dUTPase activity in vivo.

Postinhibitory rebound neurons and networks are disrupted in retrovirus-induced spongiform neurodegeneration.

Certain retroviruses induce progressive spongiform motor neuron disease with features resembling prion diseases and amyotrophic lateral sclerosis. With the neurovirulent murine leukemia virus (MLV) FrCasE, Env protein expression within glia leads to postsynaptic vacuolation, cellular effacement, and neuronal loss in the absence of neuroinflammation. To understand the physiological changes associated with MLV-induced spongiosis, and its neuronal specificity, we employed patch-clamp recordings and voltage-sensitive dye imaging in brain slices of the mouse inferior colliculus (IC), a midbrain nucleus that undergoes extensive spongiosis. IC neurons characterized by postinhibitory rebound firing (PIR) were selectively affected in FrCasE-infected mice. Coincident with Env expression in microglia and in glia characterized by NG2 proteoglycan expression (NG2 cells), rebound neurons (RNs) lost PIR, became hyperexcitable, and were reduced in number. PIR loss and hyperexcitability were reversed by raising internal calcium buffer concentrations in RNs. PIR-initiated rhythmic circuits were disrupted, and spontaneous synchronized bursting and prolonged depolarizations were widespread. Other IC neuron cell types and circuits within the same degenerative environment were unaffected. Antagonists of NMDA and/or AMPA receptors reduced burst firing in the IC but did not affect prolonged depolarizations. Antagonists of L-type calcium channels abolished both bursts and slow depolarizations. IC infection by the nonneurovirulent isogenic virus Friend 57E (Fr57E), whose Env protein is structurally similar to FrCasE, showed no RN hyperactivity or cell loss; however, PIR latency increased. These findings suggest that spongiform neurodegeneration arises from the unique excitability of RNs, their local regulation by glia, and the disruption of this relationship by glial expression of abnormal protein.

Mice lacking α1,3-fucosyltransferase 9 exhibit modulation of in vivo immune responses against pathogens.

Carbohydrate structures, including Lewis X (Lex), which is not synthesized in mutant mice that lack α1,3‐fucosyltransferase 9 (Fut9−/−), are involved in cell–cell recognition and inflammation. However, immunological alteration in Fut9−/− mice has not been studied. Thus, the inflammatory response of Fut9−/− mice was examined using the highly neurovirulent mouse hepatitis virus (MHV) JHMV srr7 strain. Pathological study revealed that inflammation induced in the brains of Fut9−/− mice after infection was more extensive compared with that of wild‐type mice, although viral titers obtained from the brains of mutant mice were lower than those of wild‐type mice. Furthermore, the reduction in cell numbers in the spleens of wild‐type mice after infection was not observed in the infected Fut9−/− mice. Although there were no clear differences in the levels of cytokines examined in the brains between Fut9−/− and wild‐type mice except for interferon‐β (IFN‐β) expression, some of those in the spleens, including interferon‐γ (IFN‐γ), interleukin‐6 (IL‐6), and monocyte chemoattractant protein‐1 (MCP‐1), showed higher levels in Fut9−/− than in wild‐type mice. Furthermore, Fut9−/− mice were refractory to the in vivo inoculation of endotoxin (LPS) compared with wild‐type mice. These results indicate that Lex structures are involved in host responses against viral or bacterial challenges.

Neurovirulence and Immunogenicity of Attenuated Recombinant Vesicular Stomatitis Viruses in Nonhuman Primates

In previous work, a prototypic recombinant vesicular stomatitis virus Indiana serotype (rVSIV) vector expressing simian immunodeficiency virus (SIV) gag and human immunodeficiency virus type 1 (HIV-1) env antigens protected nonhuman primates (NHPs) from disease following challenge with an HIV-1/SIV recombinant (SHIV). However, when tested in a stringent NHP neurovirulence (NV) model, this vector was not adequately attenuated for clinical evaluation. For the work described here, the prototypic rVSIV vector was attenuated by combining specific G protein truncations with either N gene translocations or mutations (M33A and M51A) that ablate expression of subgenic M polypeptides, by incorporation of temperature-sensitive mutations in the N and L genes, and by deletion of the VSIV G gene to generate a replicon that is dependent on trans expression of G protein for in vitro propagation. When evaluated in a series of NHP NV studies, these attenuated rVSIV variants caused no clinical disease and demonstrated a very significant reduction in neuropathology compared to wild-type VSIV and the prototypic rVSIV vaccine vector. In spite of greatly increased in vivo attenuation, some of the rVSIV vectors elicited cell-mediated immune responses that were similar in magnitude to those induced by the much more virulent prototypic vector. These data demonstrate novel approaches to the rational attenuation of VSIV NV while retaining vector immunogenicity and have led to identification of an rVSIV N4CT1gag1 vaccine vector that has now successfully completed phase I clinical evaluation. The work described in this article demonstrates a rational approach to the attenuation of vesicular stomatitis virus neurovirulence. The major attenuation strategy described here will be most likely applicable to other members of the Rhabdoviridae and possibly other families of nonsegmented negative-strand RNA viruses. These studies have also enabled the identification of an attenuated, replication-competent rVSIV vector that has successfully undergone its first clinical evaluation in humans. Therefore, these studies represent a major milestone in the development of attenuated rVSIV, and likely other vesiculoviruses, as a new vaccine platform(s) for use in humans.

Probing the Interactions Between U24 from HHV-6A/7 and Fyn-SH3 or WW Domain Proteins

U24 is a type II tail-anchored putative membrane protein unique to the Roseolovirus family, including HHV-6 and HHV-7. It contains an N-terminal proline-rich region and is believed to function by disrupting the signalling pathway in order to ensure the virus' survival. HHV-6A is a neurovirulent virus as it is often found in multiple sclerosis (MS) patients. It has also been shown to directly induce demyelination, a typical MS symptom, in naive adult marmosets1. U24 from HHV-6A shares a seven residue identity with myelin basic protein (MBP), a protein responsible for the compaction of the myelin sheath in the CNS2. U24 from HHV-7, on the other hand, does not share this sequence identity with MBP, but this virus has also been implicated in MS, though indirectly3.In order to elucidate the exact role of U24 in MS, we have investigated the interaction of this protein with other partners such as the SH3 domain from Fyn tyrosine kinase and WW domain proteins. GST pull-downs, NMR titration data and molecular dynamics simulations will be presented. The differences in binding observed for U24 from HHV-6A and -7 will shed light into the hypothesis that U24 may function by mimicking MBP, as it has been previously shown that U24 and MBP can be phosphorylated in a similar manner4.

ПЕРСИСТЕНЦИЯ БОЛЕЕ ДВУХ МЕСЯЦЕВ ВИРУСА КЛЕЩЕВОГО ЭНЦЕФАЛИТА В ЦНС И ОРГАНАХ ИММУННОЙ СИСТЕМЫ МЫШЕЙ ПОСЛЕ ИММУНИЗАЦИИ НИЗКИМИ ДОЗАМИ ХИМЕРЫ ЛАНГАТ/ДЕНГЕ4 С ПОСЛЕДУЮЩИМ ЗАРАЖЕНИЕМ ВЫСОКОВИРУЛЕНТНЫМ ШТАММОМ ВИРУСА КЛЕЩЕВОГО ЭНЦЕФАЛИТА.

High protective efficiency of inactivated purified concentrated vaccines against tick-borne encephalitis (TBE) is proven by their long-term use in clinical practice, but the need in repeated vaccinations prompts the search for alternative vaccines. In light of this, more detailed study of various aspects of postvaccination protective immunity formation is required. Our experiments on BALB/c and CBA mice characterized by different sensitivity to TBE virus have demonstrated that repeated intraperitoneal and oral immunization with low doses of Langat/Denge4 chimera can protect the animals from the disease caused by high doses of neurovirulent TBE virus, but cannot prevent virus penetration into the central nervous system (CNS) of the immunized animals and persistence more then 2 month of the infection virus in CNS and lymphoid organs. These findings suggest that this criterion should be taken into account when evaluating the efficiency of antiviral preparations, especially in case of immunization with a heterologous virus.

Role of the Nuclease Activities Encoded by Herpes Simplex Virus 1 UL12 in Viral Replication and Neurovirulence

Enzyme-dead mutations in the herpes simplex virus 1 UL12 gene that abolished its endo- and exonuclease activities only slightly reduced viral replication in cell cultures. However, the UL12 null mutation significantly reduced viral replication, suggesting that a UL12 function(s) unrelated to its nuclease activities played a major role in viral replication. In contrast, the enzyme-dead mutations significantly reduced viral neurovirulence in mice, suggesting that UL12 nuclease activities were critical for viral pathogenesis in vivo.

Monitoring West Nile virus (WNV) infection in wild birds in Serbia during 2012: first isolation and characterisation of WNV strains from Serbia

West Nile virus (WNV), a neurovirulent mosquito-transmissible zoonotic virus, has caused recent outbreaks in Europe, including Serbia from August until October 2012. Although humans can be infected, birds are the main natural WNV reservoir. To assess WNV circulation in northern Serbia, 133 wild birds were investigated. These comprised resident and migratory birds, collected between January and September 2012 in the Vojvodina province. The birds belonged to 45 species within 27 families. Blood sera (n=92) and pooled tissues from respective birds (n=81) were tested by enzyme-linked immunosorbent assay (ELISA), plaque reduction neutralisation test (PRNT) and real-time reverse transcription-polymerase chain reaction (RT-qPCR). WNV antibodies were detected in seven (8%) sera: four from Mute Swans (Cygnus olor), two from White-tailed Eagles (Haliaeetus albicillas), and one from a Common Pheasant (Phasianus colchicus). Five sera neutralised WNV but not Usutu virus. For the first time in Serbia, WNV RNA was detected by RT-qPCR in pooled tissue samples of eight respective birds. WNV RNA was also derived from an additional bird, after a serum sample resulted infective in cell culture. The total nine WNV RNA positive birds included three Northern Goshawks (Accipiter gentilis), two White-tailed Eagles, one Legged Gull (Larus michahelis), one Hooded Crow (Corvus cornix), one Bearded Parrot-bill (Panarus biramicus), and one Common Pheasant. Phylogenetic analysis of partial E region sequences showed the presence of, at least, two lineage 2 Serbian clusters closely related to those responsible for recent human and animal outbreaks in Greece, Hungary and Italy. Full genomic sequence from a goshawk isolate corroborated this data. These results confirm WNV circulation in Serbia and highlight the risk of infection for humans and horses, pointing to the need for implementing WNV surveillance programmes.

The enteroviruses: Problems in need of treatments

Specific antiviral therapy is currently not available for enterovirus (EV) infections. Poliomyelitis, EV 71 neurologic disease, and neonatal EV disease are three manifestations of EV infections that exemplify the importance of developing antivirals for EV infections. Despite tremendous strides in the effort to eradicate polio through vaccination, challenges remain, including the potential for transmission of neurovirulent vaccine-derived polioviruses which have genetically reverted from live-attenuated, oral poliovirus vaccine virus. EV 71 emerged in the late 1990 s in eastern Asia as a neurovirulent virus that causes large outbreaks of hand-foot-mouth disease, herpangina, and fever, and, in some children, meningitis, acute flaccid paralysis, and brainstem encephalitis complicated by pulmonary edema and cardiopulmonary collapse. EV infections in neonates can cause severe disease characterized by meningoencephalitis, myocarditis, pneumonitis, and/or hepatitis and coagulopathy. Prototypic agents for specific therapy of EV infections that act upon numerous potential viral targets exist. Three candidate compounds are currently in development: pleconaril (active against many EVs), V-073 (anti-poliovirus), and BTA-798 (active against many rhinoviruses and EVs). The three conditions described illustrate why development of antiviral medications for EV infections is a medically important need.

Hsp70-Dependent Antiviral Immunity against Cytopathic Neuronal Infection by Vesicular Stomatitis Virus

The major inducible 70-kDa heat shock protein (hsp70) protects against measles virus (MeV) neurovirulence in the mouse that is caused by a cell-associated noncytolytic neuronal infection. Protection is type I interferon (IFN) dependent, and we have established a novel axis of antiviral immunity in which hsp70 is released from virus-infected neurons to induce IFN-β in macrophages. The present work used vesicular stomatitis virus (VSV) to establish the relevance of hsp70-dependent antiviral immunity to fulminant cytopathic neuronal infections. In vitro, hsp70 that was constitutively expressed in mouse neuronal cells caused a modest increase in VSV replication. Infection induced an early extracellular release of hsp70 from viable cells, and the release was progressive, increasing with virus-induced apoptosis and cell lysis. The impact of this VSV-hsp70 interaction on neurovirulence was established in weanling male hsp70 transgenic and nontransgenic mice. Constitutive expression of hsp70 in neurons of transgenic mice enhanced viral clearance from brain and reduced mortality, and it was correlated with enhanced expression of type I IFN mRNA. Nontransgenic mice were also protected against neurovirulence and expressed increased type I IFN mRNA in brain when hsp70 was expressed by a recombinant VSV (rVSV-hsp70), indicating that hsp70 in the virus-infected cell is sufficient for host protection. In vitro data confirmed extracellular release of hsp70 from cells infected with rVSV-hsp70 and also showed that viral replication is not enhanced when hsp70 is expressed in this manner, suggesting that hsp70-mediated protection in vivo is not dependent on stimulatory effects of hsp70 on virus gene expression.

Identification of a Neurovirulence Factor from Marek's Disease Virus

In addition to tumors, Marek's disease (MD) virus (MDV) can induce a variety of syndromes linked to the central nervous system. In fact, early descriptions of MD suggested that it was a condition affecting mainly the nervous system. Cytokines and other immune-related genes have been suggested to play a crucial role in MDV-mediated neuropathology, but the mechanisms behind the viral-induced neurologic dysfunction are still poorly understood. In the present study we have used reverse genetic strategies to show that pp14 is not involved in the oncogenic phenotype of MDV1 and is not required for viral replication; however, we provide evidence indicating that the absence of pp14 expression is correlated with increased survival of MDV1-infected chickens, and that its expression is associated with enhanced viral neurovirulence. Our data identify for the first time pp14 as a neurovirulence factor from MDV1 and open the possibility to investigate the molecular mechanisms by which pp14 mediates the damage to the avian nervous system.

Differential type 1 interferon‐regulated gene expression in the brain during AIDS: interactions with viral diversity and neurovirulence

The lentiviruses, human and feline immunodeficiency viruses (HIV-1 and FIV, respectively), infect the brain and cause neurovirulence, evident as neuronal injury, inflammation, and neurobehavioral abnormalities with diminished survival. Herein, different lentivirus infections in conjunction with neural cell viability were investigated, concentrating on type 1 interferon-regulated pathways. Transcriptomic network analyses showed a preponderance of genes involved in type 1 interferon signaling, which was verified by increased expression of the type 1 interferon-associated genes, Mx1 and CD317, in brains from HIV-infected persons (P<0.05). Leukocytes infected with different strains of FIV or HIV-1 showed differential Mx1 and CD317 expression (P<0.05). In vivo studies of animals infected with the FIV strains, FIV(ch) or FIV(ncsu), revealed that FIV(ch)-infected animals displayed deficits in memory and motor speed compared with the FIV(ncsu)- and mock-infected groups (P<0.05). TNF-α, IL-1β, and CD40 expression was increased in the brains of FIV(ch)-infected animals; conversely, Mx1 and CD317 transcript levels were increased in the brains of FIV(ncsu)-infected animals, principally in microglia (P<0.05). Gliosis and neuronal loss were evident among FIV(ch)-infected animals compared with mock- and FIV(ncsu)-infected animals (P<0.05). Lentiviral infections induce type 1 interferon-regulated gene expression in microglia in a viral diversity-dependent manner, representing a mechanism by which immune responses might be exploited to limit neurovirulence.

Characteristics and functional roles of UL14 protein of herpesviruses

The UL14 gene of herpesvirus belongs to the long UL region, which is a late expression gene. The protein encoded by the UL14 gene is a minor component of the virion tegument and plays a major role in virus replication by enhancing effects on the envelope and capsid transport to the nucleus. It is also involved in virus maturation, neurovirulence, antiapoptotic activity and regulation of the expression of IE gene. The subcellular localization of the UL14 protein distributed differently at different times. In this review, the characters of the UL14 gene and the characteristics and functions of UL14 protein are described.

Herpes Simplex Virus 2 Expresses a Novel Form of ICP34.5, a Major Viral Neurovirulence Factor, through Regulated Alternative Splicing

Herpes simplex virus 1 (HSV-1) and HSV-2, two closely related neurotropic human herpesviruses, achieve neurotropism through ICP34.5, a major viral neurovirulence factor. In this report, in addition to the full-length 38-kDa protein (ICP34.5α), we identified a 28-kDa novel form of ICP34.5 (ICP34.5β) in HSV-2-infected cells. ICP34.5β is translated from unspliced ICP34.5 mRNA, with the retained intron introducing a premature stop codon. Thus, ICP34.5β lacks the C-terminal conserved GADD34 domain but includes 19 additional amino acids encoded by the intron. Although a fraction of both HSV-2 ICP34.5 proteins are detected in the nucleolus, ICP34.5α is predominantly located in cytoplasm, and ICP34.5β is mainly detected more diffusely in the nucleus. ICP34.5β is unable to counteract PKR-mediated eIF2 phosphorylation but does not interfere with ICP34.5α's function in this process. Efficient expression of ICP34.5β in cell culture assays is dependent on viral infection or expression of ICP27, a multifunctional immediate-early gene. The effect of ICP27 on the ICP34.5β protein level is attributed to its selective inhibition of ICP34.5 splicing, which results in increased expression of ICP34.5β but a reduced level of ICP34.5α. The C- terminal KH3 domain but not the RNA binding domain of ICP27 is required for its specific inhibition of ICP34.5 splicing and promotion of ICP34.5β expression. Our results suggest that the expression of ICP34.5α and ICP34.5β is tightly regulated in HSV-2 and likely contributes to viral pathogenesis.

The Amino Terminus of Herpes Simplex Virus 1 Glycoprotein K Is Required for Virion Entry via the Paired Immunoglobulin-Like Type-2 Receptor Alpha

The herpes simplex virus 1 (HSV-1) glycoprotein K (gK)/UL20 protein complex is incorporated into virion envelopes and cellular membranes and functions during virus entry and cell-to-cell spread. To investigate the role of gK/UL20 in the context of a highly neurovirulent virus strain, the HSV-1(McKrae) genome was cloned into a bacterial artificial chromosome plasmid (McKbac) and utilized to construct the mutant virus McK(gKΔ31-68), carrying a 37-amino-acid deletion within the gK amino terminus. The McKbac virus entered efficiently into Chinese hamster ovary (CHO) cells constitutively expressing HSV-1 human receptors, nectin-1, herpesvirus entry mediator (HVEM), or paired immunoglobulin-like type-2 receptor alpha (PILRα). In contrast, the McK(gKΔ31-68) virus failed to enter into CHO-PILRα cells, while it entered CHO cells expressing HVEM and nectin-1 more efficiently than the McKbac virus. Both McKbac and McK(gKΔ31-68) viruses entered all CHO cells expressing HSV-1 receptors via a pH-independent pathway. The HSV-1(F) gBΔ28syn mutant virus, encoding a carboxyl-terminal truncated gB, causes extensive cell fusion. Previously, we showed that the gKΔ31-68 amino acid deletion abrogated gBΔ28syn virus-induced cell fusion, indicating that the amino terminus of gK is required for gB-mediated virus-induced cell fusion (V. N. Chouljenko, A. V. Iyer, S. Chowdhury, D. V. Chouljenko, and K. G. J. Kousoulas, Virology 83:12301-12313, 2009). Surprisingly, the gKΔ31-68/gBΔ28syn virus caused extensive fusion of CHO-nectin-1 cells but limited cell fusion of CHO-PILRα cells. Coimmunoprecipitation experiments revealed that both gK and PILRα bound gB in infected cells. Collectively, these results indicate that the amino terminus of gK is functionally and physically associated with the gB-PILRα protein complex and regulates membrane fusion of the viral envelope with cellular membranes during virus entry as well as virus-induced cell-to-cell fusion.

An attenuating mutation in a neurovirulent Sindbis virus strain interacts with the IPS-1 signaling pathway in vivo

An attenuating mutation in a neurovirulent Sindbis virus strain interacts with the IPS-1 signaling pathway in vivo

An attenuating mutation in a neurovirulent Sindbis virus strain interacts with the IPS-1 signaling pathway in vivo

An attenuating mutation in a neurovirulent Sindbis virus strain interacts with the IPS-1 signaling pathway in vivo