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Biomedical subjects

H J Field

Publications and source records attributed to H J Field.

At least 91 records · Page 5Linked to original sources
PubMed1984

A quantitative study of the effects of several nucleoside analogues on established herpes encephalitis in mice.

Mice with established herpes encephalitis were used to compare the effects of chemotherapy using three different nucleoside analogues. Encephalitis was produced by intranasal inoculation of a type 1 strain of herpes simplex virus. Without chemotherapy all mice died within 5 to 7 days of inoculation. Oral acyclovir (ACV) was a successful preventative measure if commenced within 2 days of inoculation but much less effective if the onset of treatment was further delayed. From the third day, when central nervous system infection had definitely become established, ACV only reduced mortality if given intraperitoneally (i.p.) at regular 6-hourly intervals. Comparison with bromovinyldeoxyuridine (BVdU) and the new nucleoside analogue dihydroxypropoxymethylguanine (DHPG) using the same 6-hourly i.p. regimen revealed that BVdU was poorly effective, despite better activity in vitro, whereas DHPG was the most successful. Virus was rapidly eradicated from all parts of the brain by DHPG therapy, and by day 10, no infectious virus remained in the brains of treated mice, no virus antigens were observed and no trace of virus DNA could be detected in neural tissues by Southern blotting.

Acyclovir↗
PubMed1984

An animal model of ocular herpes. Keratitis, retinitis and cataract in the mouse.

Acute ocular infection followed both intracerebral and intranasal inoculation of herpes simplex type I virus (HSVI) in mice. Eye infections were a terminal complication of fatal encephalitis. After intracerebral inoculation HSVI spread directly along the optic nerves to infect the retina provoking a necrotizing retinitis. In contrast after intranasal inoculation, HSVI spread via the fifth cranial nerve to the anterior chamber of the eye producing keratitis and uveitis. Necrotizing retinitis was also produced by intracerebral inoculation of mice with a drug-resistant mutant HSVI known to have relatively low neurovirulence. These animals developed only mild encephalitis but this was associated with florid retinitis. The mice survived cerebral infection with the mutant virus and several weeks after initial inoculation cataracts were observed. There was no evidence, at any time, of virus infection of lens epithelium and cataracts appeared to be a non-specific consequence of retinal injury. It is suggested that these examples of murine ocular infection provide animal models for herpetic eye lesions in man and thus may elucidate the pathogenesis of herpetic keratitis, retinitis and cataract.

Animals↗
PubMed1983

The distribution of herpes simplex type 1 antigen in mouse central nervous system after different routes of inoculation.

Herpes simplex type 1 virus was inoculated into 3-week-old mice via four different routes; intracerebral, intravenous, intranasal and directly into the sciatic nerve. Virus antigen-containing cells in the central nervous system were identified by both an immunofluorescence and immunoperoxidase method. The portal of entry of virus into the CNS appeared to be the major determinant of distribution of virus antigen. Direct haematogenous seeding of virus into the CNS was not proven. It seems probable that infection was first established in sensory ganglia. Within the CNS, regions of high virus antigen concentration paralleled high cell density suggesting cell to cell spread. Consistent involvement of certain neuron groups may be due to their selective vulnerability. These animal experiments provide some explanation for the patterns of CNS herpetic infection observed in man.

Animals↗
PubMed1983

Acquired resistance to acyclovir: laboratory phenomenon or clinical problem?

In tissue culture, herpes simplex readily acquires resistance to nucleoside analogue inhibitors such as acyclovir. The two possible sites where resistance may develop are in the thymidine kinase (TK) and in the DNA polymerase genes; the commonest in vitro mutant is TK negative (TK-), although some strains may induce low levels of enzyme activity. The characteristics and modes of selection of these mutants are discussed, together with a preliminary consideration of the possible situation in man when antiviral drugs come to be more widely used.

Acyclovir↗
PubMed1983

A perspective on resistance to acyclovir in herpes simplex virus.

Herpes simplex virus can acquire resistance to acyclovir by mutation leading to change in either of the two virus-specified enzymes involved in the mode of action of the drug. Thymidine kinase may be completely lost yet the virus is able to replicate normally, at least in vitro. Resistant variants arise readily in tissue culture but, in contrast, resistance does not emerge quickly in experimentally infected animals or in man undergoing chemotherapy. Thymidine kinase defective mutants are generally attenuated but have accounted for several cases of resistance in immunosuppressed patients. While resistance does not appear to be a clinical problem at the moment, consideration of the properties of laboratory mutants suggests that eventually resistance may be encountered among human infections.

Acyclovir↗
PubMed1983

Pathogenesis of mouse scrapie: evidence for spread of infection from central to peripheral nervous system.

The onset of replication has been studied in spinal cord, dorsal root ganglia and spinal nerves of CW mice infected intraperitoneally with the 139A strain of scrapie. The patterns obtained suggest a centrifugal spread of infection from central to peripheral nervous systems. Infectivity titres in the peripheral nervous system reached a plateau long before the end of the incubation period, and the maximum titres were much lower than in the central nervous system. This suggests that there is a restriction of replication in the peripheral nervous system similar to that already known in extraneural tissues.

Animals↗
PubMed1982

Isolation and characterization of acyclovir-resistant strains of herpes simplex virus.

A number of clinical studies have documented herpes simplex infections which appear to be resistant to nucleoside analogs; these include idoxuridine [1,2] and acyclovir [3]. Few, if any of the viruses isolated from such patients have yet been thoroughly characterized. We have isolated a number of acyclovir-resistant mutants by selection for resistance in tissue culture. The study of the biochemical and biological properties of these mutants has given some insight into the likely nature of resistant clinical strains. We have devised a number of simple tests to allow classification of laboratory mutants. We also draw attention to some of the difficulties the clinical virologist may encounter when analyzing putative resistant virus isolated from treated patients.

Acyclovir↗
PubMed1982

Role of neutralizing antibodies and T-cells in pathogenesis of herpes simplex virus infection in congenitally athymic mice.

Congenitally athymic nude mice were infected with 10(4) p.f.u. herpes simplex type 1 (strain SC16). Following the passive transfer of neutralizing monoclonal antibodies (AP7, AP8 and AP12) it was observed that AP7 alone reduced the virus infectivity in the nervous system; AP8 and AP12 failed to protect mice probably due to poor in vivo binding to the neutralization site on the virus. Latent ganglionic infection could be established in nude mice following adoptive transfer of optimum number (2 x 10(7) cells/mouse) of immune lymph node cells from day 7 herpes virus-infected hairy immunocompetent donor mice. Moreover, in some of the immune lymph node cell protected nudes, latency could be maintained even in complete absence of neutralizing antibodies. Results of ear-ablation experiments revealed that removal of primary source of infection after day 5 of infection reduced the amount of virus in the ganglia and spinal cord. Acute neurological infection was not detected following transfer of protective anti-gp-D neutralizing antibody (LP2) in combination with removal of infected pinna. These data suggest that continuous seeding of virus occurs in related ganglia via the axonal route from infected ear pinna. It appears that local T-cell-mediated immune mechanisms are involved in maintenance of latency.

Animals↗
PubMed1982

Isolation of bromovinyldeoxyuridine-resistant strains of herpes simplex virus and successful chemotherapy of mice infected with one such strain by using acyclovir.

Several strains of herpes simplex virus which were resistant to bromovinyldeoxyuridine were isolated by passaging the virus in the presence of the drug in tissue culture. The resistance of the majority of isolates was accounted for by their reduced ability to induce the enzyme thymidine kinase. These strains were co-resistant to acyclovir, but showed reduced pathogenicity in mice. However, another type of bromovinyldeoxyuridine-resistant virus was isolated which induced normal levels of thymidine kinase and retained virulence for mice. This resistant virus was sensitive to acyclovir and was successfully treated using oral acyclovir therapy.

Acyclovir↗
PubMed1982

Atypical patterns of neural infection produced in mice by drug-resistant strains of herpes simplex virus.

Mice inoculated intracerebrally (i.c.) with a mutant strain of HSV were found to develop cataracts 1 to 2 months after inoculation. Cataract formation was subsequently shown to follow an acute retinitis which commenced within 1 week of inoculation. The mutant had been selected for high resistance to the nucleoside analogue acyclovir and has been shown previously to be defective in the induction of thymidine kinase and also to express an altered DNA polymerase. The LD50 for mice inoculated i.c. was greater than 10(5) p.f.u. compared with approx 7 p.f.u. for the parental strain. Studies of virus replication following i.c. inoculation with a sublethal dose of the mutant revealed that only small amounts of infectious virus were produced in the brain, but during a period from 6 to 12 days after inoculation vigorous replication occurred in retinal tissue, producing very high titres of virus.

Acyclovir↗
PubMed1982

Pathogenesis of herpes simplex virus in congenitally athymic mice: the relative roles of cell-mediated and humoral immunity.

Athymic nude (nu/nu) mice were inoculated in the ear pinna with 10(4) p.f.u. herpes simplex virus type 1 (strain SC 16). Initially, the virus was observed to replicate in the pinna, spreading via a neurological route to the dorsal root ganglia, spinal cord, brain and adrenal glands. Following the transfer of lymphoid cells from day 7 herpesvirus-infected hairy immunocompetent donors into infected nude mice, virus was not isolated from the pinna and nervous system of the majority of the mice. The passive transfer of neutralizing polyclonal anti-herpesvirus serum or neutralizing monoclonal anti-gp D serum did not reduce infectivity in the pinna, but markedly reduced the amount of virus in the ganglia and spinal cord. These data suggest that neutralizing antibodies play an important role in restricting the movement of virus to the nervous system, whereas cell-mediated immune (CMI) mechanisms are essential for eliminating virus from the pinna.

Animals↗
PubMed1982

Development of clinical resistance to acyclovir in herpes simplex virus-infected mice receiving oral therapy.

Mice inoculated in the ear pinna with herpes simplex virus were treated effectively by including 1 mg of acyclovir per ml in the drinking water. During a 5-day course of treatment the development of resistance was not readily apparent. However, when a suboptimal therapeutic dose was used and virus was repeatedly inoculated into further mice undergoing therapy, the infection became completely refractory to treatment by passage 4. Some of the viruses isolated exhibited reduced ability to induce thymidine kinase, and this appeared to account at least in part for the development of resistance. However, the viruses isolated from the tissues of such mice comprised complex mixtures of strains with widely differing in vitro susceptibilities to acyclovir. The properties of these virus yields gave an indication of the likely nature of resistance to nucleoside analogs in humans and suggested some difficulties which may be encountered when clinical specimens are analyzed.

Acyclovir↗
PubMed1981

Altered substrate specificity of herpes simplex virus thymidine kinase confers acyclovir-resistance.

Acyclovir (9-[2-hydroxyethoxymethyl]guanine or ACV) is a nucleoside analogue with considerable potential for the treatment of herpes simplex virus (HSV) infections in man. Two virus-coded enzymes are important in the mechanism of action of this drug: thymidine kinase (TK) which initiates its activation by converting it to the monophosphate and DNA polymerase whose action is inhibited by ACV triphosphate. Changes in either gene may confer resistance, but all reported mutations in the TK gene have resulted in failure of the resistant virus to induce appreciable levels of the enzyme. Such TK- mutants arise readily in tissue culture systems where the enzyme is non-essential for virus replication, but in animals they show considerably reduced pathogenicity and neurovirulence. We now describe the isolation of a resistant mutant which induces a TK of altered substrate specificity and we show that this virus retains pathogenicity for mice with only a slight attenuation of neurovirulence.

Acyclovir↗
PubMed1981

Effects of oral treatment with acyclovir and bromovinyldeoxyuridine on the establishment of maintenance of latent herpes simplex virus infection in mice.

Mice infected with herpes simplex virus (HSV) were treated (separately) with the nucleoside analogues acyclovir or bromovinyldeoxyuridine by incorporating the drugs in the drinking water. This method of treatment was found to be effective for both drugs and compared favourably with intraperitoneal injection. Prompt treatment with either compound could prevent the establishment of latent infections but latent infections once established were intractable using prolonged courses of oral administration.

Acyclovir↗