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Biomedical subjects

R W Price

Publications and source records attributed to R W Price.

At least 109 records · Page 6Linked to original sources
PubMed1983

Replication of thymidine kinase deficient herpes simplex virus type 1 in neuronal cell culture: infection of the PC 12 cell.

Replication of a thymidine kinase deficient (TK-) mutant of herpes simplex virus type 1 (HSV-1) was compared to replication of its parental TK+ strain in the PC 12 cell. This is a cell which ceases cell division and undergoes neuron-like morphological and physiological differentiation in the presence of nerve growth factor (NGF). No difference between mutant and parental strain replication was detected either when these cells were infected in the proliferative state or while maintained under the influence of NGF. Neither viral TK nor enhanced cellular TK activity was detected during TK- HSV-1 replication, which proceeded in the presence of selective antiviral drugs that inhibited TK+ HSV-1 viral replication. Moreover, thymidylate synthetase was inhibited early in TK- infection, and reutilization of thymine nucleotides derived from degraded cellular DNA was not detected. Under the conditions of these in vitro studies, increased production of dTTP as a result of enhanced TK activity did not appear to be rate-limiting, despite the non-dividing "differentiated" state of the PC 12 cell.

Animals↗
PubMed1983

Preservation of catecholamine uptake and release in herpes simplex virus type 1-infected PC12 cells.

The PC12 cell line, which is derived from a rat pheochromocytoma and possesses a number of 'differentiated' neuronal properties, was used to characterize the effect of herpes simplex virus type 1 (HSV-1) infection on the uptake and release of catecholamines. Both the uptake of [3H]norepinephrine and the content and K+-induced release of endogenous catecholamines were remarkably preserved during the course of productive infection. HSV-1 infection is thus selective in its effects on the host cell and certain specialized functional properties may be retained in the face of otherwise profound metabolic alterations.

Animals↗
PubMed1982

Quantitative autoradiographic mapping of herpes simplex virus encephalitis with a radiolabeled antiviral drug.

2'-Fluoro-5-methyl-l-beta-D-arabinosyluracil (FMAU) labeled with carbon-14 was used to image herpes simplex virus type 1-infected regions of rat brain by quantitative autoradiography. FMAU is a potent antiviral pyrimidine nucleoside which is selectively phosphorylated by virus-coded thymidine kinase. When the labeled FMAU was administered 6 hours before the rats were killed, the selective uptake and concentration of the drug and its metabolites by infected cells (defined by immunoperoxidase staining of viral antigens) allowed quantitative definition and mapping of HSV-1-infected structures in autoradiograms of brain sections. These results show that quantitative autoradiography can be used to characterize the local metabolism of antiviral drugs by infected cells in vivo. They also suggest that the selective uptake of drugs that exploit viral thymidine kinase for their antiviral effect can, by appropriate labeling, be used in conjunction with clinical neuroimaging techniques to define infected regions of human brain, thereby providing a new approach to the diagnosis of herpes encephalitis in man.

Animals↗
PubMed1982

Herpes simplex virus infection of isolated autonomic neurons in culture: viral replication and spread in a neuronal network.

Cultures of isolated neurons, derived from the superior cervical ganglion (SCG) of the newborn rat and maintained in the absence of nonneuronal cells, were infected with herpes simplex virus (HSV) type 1. By phase-contrast microscopy, including time-lapse cinematography, cytopathologic changes appeared first in neuronal cell bodies and only approximately 24 hours later were axonal abnormalities detectable. Despite low yields of viral progeny, infection spread readily within the two-dimensional network of neurons and their processes. Immunoperoxidase staining for viral antigens confirmed the replication and spread of virus and revealed that antigen extended along axons during infection. Antiviral antibody added to the overlay medium slowed but did not prevent the spread of infection, indicating that virus passed from neuron to neuron over axonal pathways. Despite alteration of neuronal macromolecular synthesis early in infection, axonal transport is apparently preserved long enough to allow propagation of virus over interconnecting neural pathways.

Animals↗
PubMed1982

Interferon protects neurons in culture infected with vesicular stomatitis and herpes simplex viruses.

The protective effect of crude rat interferon against infection by vesicular stomatitis virus (VSV) and herpes simplex virus (HSV) was assessed in two culture systems: the PC12 cell line and dissociated rat neurons derived from the superior cervical ganglion (SCG). Interferon was induced in rat embryo cells by inactivated Newcastle disease virus, and its effect was assessed by reduction of viral yields and prevention of viral cytopathology. Interferon protected PC12 cells, both in the presence and absence of nerve growth factor (NGF), against infection by both viruses, although at differing concentrations: protection against VSV was noted at approximately a 10-fold lower interferon concentration than that required to inhibit HSV infection. Dissociated SCG neurons were also protected, but higher interferon concentrations were required. These results demonstrate that the antiviral state can be established in neurons in response to interferon.

Animals↗
PubMed1981

Tyrosine hydroxylase activity in the superior cervical ganglion during herpes simplex virus infection: correlation with viral titers and viral antigen.

The activity of tyrosine hydroxylase (TH) was measured in the superior cervical ganglion (SCG) of the mouse during herpes simplex virus (HSV) infection. TH activity remained at control levels or actually increased during acute infection at a time when viral titers of SCG homogenates were at their peak and viral antigen was detected in from one-third to one-half of ganglionic neurons. A rapid decline in TH activity followed and coincided with falling viral titers, disappearance of viral antigen and replacement of neurons by inflammatory cells. Immunization partially prevented this reduction of TH activity. In addition, when mice were immunosuppressed by cyclophosphamide, TH activity was relatively preserved early in the course of infection despite high viral titers in the ganglion and the presence of viral antigen and histopathological alterations in nearly 100% of neurons. These results suggest that a cellular 'luxury function', in this case TH activity, can be preserved and perhaps even augmented during neuronal HSV infection. Indeed, activity of this enzyme may persist until late into the acute phase of infection, perhaps up to the point of cell death induced either by immune-mediated or direct virus-induced cell lysis.

Animals↗
PubMed1981

Multifocal varicella-zoster virus leukoencephalitis temporally remote from herpes zoster.

Two patients with cancer, one with Hodgkin's disease and the other with a granulosa cell tumor of the ovary, developed a progressive, eventually fatal infection of the central nervous system exhibiting multifocal symptoms and signs. Pathologically, gross abnormalities of the brain resembled those in progressive multifocal leukoencephalopathy (PML), with discrete and confluent plaque-like lesions concentrated in the white matter, particularly along the gray-white junction. Microscopically, pathological changes differed distinctly from those associated with PML; in addition to confluent foci of white matter injury characterized by early demyelination and subsequent necrosis, prominent Cowdry type A eosinophilic intranuclear inclusions were noted in oligodendrocytes, astrocytes, and neurons. By electron microscopy, intranuclear spherical particles consistent in size and appearance with herpesvirus nucleocapsids were found within the lesions. Immunoperoxidase studies detected varicella-zoster virus (VZV) antigens in infected cells, implicating this virus as the responsible agent despite a lapse of many months between the cutaneous herpes zoster and onset of cerebral symptoms in both patients.

Adult↗
PubMed1981

Resistance of peripheral autonomic neurons to in vivo productive infection by herpes simplex virus mutants deficient in thymidine kinase activity.

We used a model involving acute and latent herpes simplex virus (HSV) infections of mouse superior cervical ganglia to assess in vivo neuronal infections with two thymidine kinase-deficient (TK-) mutants of HSV type 1. Despite replication of the TK- HSV strains at the site of inoculation in the eyes, little if any viral replication occurred in the superior cervical ganglia, as assessed by the viral titers of ganglion homogenates, viral antigens in tissue sections, and histopathological evidence of cytopathology or inflammation. Cyclophosphamide-induced immunosuppression and treatment with 6-hydroxydopamine, which enhanced productive infections of superior cervical ganglia with TK+ HSV did not induce TK- HSV ganglionic infections. Latent TK- HSV infections were not detected by cocultivation of ganglion explants. Efforts to infect ganglia in culture after they were removed from animals indicated that superior cervical ganglia, and particularly their neuronal elements, resisted productive TK- HSV infection. These results supported the hypothesis that viral thymidine kinase facilitates acute and reactivated productive HSV infections of neurons.

Animals↗
PubMed1980

Progressive multifocal leukoencephalopathy (PML): in vitro cell-mediated immune responses to mitogens and JC virus.

Cell-mediated immunity was studied by in vitro tests in seven patients with progressive multifocal leukoencephalopathy (PML). Lymphocyte proliferation in response to mitogenic stimulation was reduced to a variable degree in all patients, indicating a general impairment of cell-mediated immune responsiveness, although mitogen-induced production of the lymphokine migration inhibitory factor (LIF) was normal in most cases. Cell-mediated immunity to JC virus (JCV) was assessed by LIF production in response to JCV antigen. In the six PML patients tested, LIF production with JCV antigen was absent despite the presence of antibody to JCV in serum. This contrasted with positive LIF production in seropositive normal individuals and patients and patients with other diseases. These results provide the first in vitro evidence of a depressed cell-mediated immune response to JCV in patients with PML, and support the hypothesis that PML is accompanied by a selective marked deficiency in cellular response to this virus in association with a general depression of cell-mediated immunity of variable severity.

Adult↗
PubMed1979

Route of infection, systemic host resistance, and integrity of ganglionic axons influence acute and latent herpes simplex virus infection of the superior cervical ganglion.

The character of acute and latent herpes simplex virus (HSV) infection of the superior cervical ganglion (SCG) in mice depended on the route by which the virus reached the ganglion, the level of systemic host resistance, and the integrity of postganglionic nerves. Prevention of ganglionic infection by postganglionic neurectomy carried out before intraocular (i.o.) virus challenge established the importance of the neural route in the development of SCG infection. However, hematogenous virus dissemination also led to SCG infection although with reduced frequency compared to that with i.o. inoculation. Enhanced host systemic antiviral resistance had two divergent effects on ganglionic infection depending on the dose and timing of virus inoculation. Thus, both acute and latent ganglionic infections were concomitantly reduced when resistant C57B1/6 mice were challenged with low doses of virus or when less resistant BALB/c mice were actively immunized 1 week before virus challenge. On the other hand, when resistant mice were challenged with high doses of virus or when either active or passive (antibody) immunization was delayed long enough to assure viral access to the ganglion, intraganglionic viral replication during the acute phase of infection was reduced, but the prevalence of subsequent latent infection was either unaffected or actually enhanced. Postganglionic neurectomy, performed after virus had reached the ganglion, altered the course of SCG infection in a direction opposite that of immunization, augmenting the acute phase of viral replication while reducing latency. In athymic nude mice and mice immunosuppressed with cyclophosphamide, intraganglionic viral replication was prolonged. These results emphasize that host factors both extrinsic and intrinsic to the SCG modify the course of ganglionic infection.

Acute Disease↗
PubMed1978

Reactivation of latent herpes simplex virus infection of the autonomic nervous system by postganglionic neurectomy.

Latent herpes simplex virus infection of the superior cervical autonomic ganglion was reactivated in vivo by postganglionic neurectomy. Two methods were used to demonstrate viral reactivation: (i) recovery of infectious herpes simplex virus in ganglion homogenates and (ii) acceleration of virus expression in ganglion explants in culture. Both the percentage of mice exhibiting reactivated ganglion infection and the viral titers detected in ganglia increased when neurectomized mice were treated with cyclophosphamide. Antithymocyte serum treatment prolonged the time course over which neurectomy-induced virus could be detected, but neither antithymocyte serum nor cyclophosphamide reactivated herpes simplex virus in the absence of neurectomy. These results demonstrate that postganlionic neurectomy provides a specific stimulus for herpes simplex virus reactivation and that cell-mediated immune defense are involved in the highly efficient elimination of reactivated virus from the ganglion in vivo.

Animals↗
PubMed1977

Effect of immunization on acute and latent infections of vaginouterine tissue with herpes simplex virus types 1 and 2.

Inoculation of mice with herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) by the vaginal route resulted in viral shedding during the acute phase of the infection and the development of a latent infection in vaginouterine tissue lasting up to one year in greater than 25% of the animals. Immunization with either serotype of HSV markedly reduced viral shedding when animals were subsequently challenged with the homologous serotype, but immunization with HSV-2 was significantly less effective in preventing the development of a latent infection in the vaginouterine tissue after challenge than was immunization with HSV-1.

Animals↗
PubMed1975

Latent infection of sensory ganglia with herpes simplex virus: efficacy of immunization.

Mice were used to test the efficacy of active immunization in preventing latent infection of local sensory ganglia that follows inoculation of superficial epithelial surfaces with herpes simplex virus. Substantial but not complete protection was observed in animals immunized and challenged with herpes simplex virus type 1, but no protection was noted in animals immunized and challenged with herpes simplex virus type 2. Latent ganglionic infection can develop in immunized animals despite the presence of high titers of neutralizing antibody.

Animals↗
PubMed1974

Latent ganglionic infection with herpes simplex virus types 1 and 2: viral reactivation in vivo after neurectomy.

Inoculation of the cornea, lip, or footpad of mice with herpes simplex virus type 1 resulted in a latent infection of the local sensory ganglia. Inoculation of the vagina and cervix with herpes simplex virus type 2, as well as type 1, also induced a latent ganglionic infection. With the use of sciatic nerve section as a stimulus, a reproducible model of viral reactivation in vivo was established.

Animals↗