Simian varicella virus infection in African and Asian monkeys. The potential for development of antivirals for animal diseases.
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Biomedical subjects
Publications and source records attributed to K F Soike.
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We used polymerase chain reaction to analyze the prevalence and distribution of latent simian varicella virus (SVV) in ganglionic and nonganglionic tissues from nine African green monkeys experimentally infected with SVV. Primers specific for three different regions of the SVV genome were used for amplification. SVV DNA sequences were detected in trigeminal ganglia from seven of nine monkeys and in thoracic ganglia from seven of nine monkeys. Analysis of DNA from nonneuronal tissues of three monkeys and from adrenal glands of nine monkeys revealed the presence of SVV-specific sequences in the adrenal gland of one monkey. The results indicate that, like human varicella, SVV becomes latent primarily in ganglia at multiple levels of the neuraxis, and more than one region of the SVV genome is present in latently infected ganglia. SVV latency in primates may be a useful model for varicella latency in humans.
Two species of primates, Owl and African green monkeys, were inoculated intracerebrally with either the neurotropic mouse hepatitis virus JHM or the putative multiple sclerosis brain coronavirus isolate SD. These viruses caused an acute to subacute panencephalitis and/or demyelination in the infected animals. The course of pathogenesis and sites of detected viral RNA and antigen was dependent both on animal species and virus strain but the results clearly showed that these viruses replicated and disseminated in the central nervous system (CNS) of these primates. This study suggests that human CNS may be susceptible to coronavirus infection.
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Approximately 80 baboon deaths were caused by encephalomyocarditis virus (EMCV) infection in a 3060 member research and production colony. The epizootic extended over a 9-month period and occurred in baboons ranging from 1 day to 22 years of age. Acute death was the most common history. When clinical disease was detected, it was characterized by labored respiration associated with acute congestive heart failure. The salient necropsy findings were pulmonary congestion and edema, hydropericardium, hydrothorax, ascites, lymph node and splenic hypertrophy, and pale white-to-tan mottled hearts. The most significant histologic lesion was nonsuppurative necrotizing myocarditis. Placental infection with fetal loss occurred. Diagnosis was confirmed by light microscopy, transmission electron microscopy, virus culture, and serology. Rarely, EMCV-induced antibody persisted in surviving baboons for more than 24 months. EMCV-infected feral rats were the probable source of the virus and their control stopped the epizootic. No EMCV neutralizing antibody was detected in colony support personnel or chimpanzees.
The toxicity of a new antiviral agent, 6-methoxypurine arabinoside (ara-M), as a selective and potent inhibitor against varicella-zoster virus, was investigated after intravitreal injection in rabbit eyes. Intravitreal doses of ara-M ranging from 20 micrograms to 400 micrograms produced no retinal toxicity, as assessed by electroretinography and light and transmission electron microscopy. These data suggest a potential role for intravitreal ara-M in the antiviral treatment of varicella-zoster viral retinitis.
Two preparations of silicone gels were evaluated as long-term vitreous substitutes in the vitrectomized and lensectomized eyes of primates. Both preparations were injected in liquid form and polymerized in the vitreous cavity. There was no toxic effect on the ocular structures up to 13 months after implantation. Fundus examination and fluorescein angiography were possible through the less rigid gel, whereas the preparation with higher rigidity consistently appeared cloudy.
We investigated the toxicity of single doses of intravitreally administered interferon alpha-2a in albino rabbits. Following injection of interferon in doses of 40,000, 80,000, 160,000, 320,000, and 640,000 IU/0.1 mL, no significant histologic changes were detected by light and electron microscopy. Photopic and scotopic electroretinography showed no alteration of retinal function.
Five African green monkeys inoculated intratracheally with 7.5 x 10(3) to 1.4 x 10(5) plaque-forming units of simian varicella virus (SVV) were subjected to clinical, laboratory, pathologic, and virologic analyses to study the pathogenesis of acute varicella. All animals developed viremia and rash and were sacrificed 8 to 11 days post-infection. No serum was available for postmortem serologic studies. Examination of multiple organs for pathologic changes and for SVV-specific antigen and nucleic acid revealed inflammation, hemorrhagic necrosis, and intranuclear Cowdry A inclusions in liver, lung, lymph node, and spleen; mild inflammation without necrosis in adrenal gland, kidney, and bone marrow, and SVV-specific antigen and nucleic acids in all viscera examined. No pathologic changes, SVV antigen or nucleic acids were detected in the spinal cord or in the brain from any of the monkeys. Ganglia revealed mild inflammation but no necrosis, and intranuclear inclusion bodies in non-neuronal cells of one trigeminal ganglion; SVV antigen and nucleic acids were detected in both non-neuronal and neuronal cells in ganglia. The pathologic and virologic findings in viscera are consistent with those described in viscera of humans with disseminated zoster, but the mild inflammatory changes in ganglia during acute simian varicella infection contrast with the extensive hemorrhagic necrosis and intranuclear inclusion bodies seen in human ganglia after disseminated varicella or zoster. Nevertheless, these studies show that ganglia become infected with varicella virus during primary infection, although the route of primary ganglionic infection remains to be determined, and indicate the possible usefulness of the SVV model to study varicella pathogenesis in humans.
(S)-1-[3-Hydroxy-2-(phosphonylmethoxy)propyl]cytosine (S-HPMPC) was able to prevent simian varicella infection in African green monkeys inoculated intratracheally with virus. A dose of 50 mg/S-HPMPC/kg administered intravenously was shown to prevent the development of rash, reduce viremia and protect the monkeys from death. The 50 mg/kg dose was effective when treatments initiated on day 2 post-infection (p.i.) was given as ten daily doses of 5 mg/kg, as 10 mg/kg administered on five days on an alternate-day schedule, as two 25 mg/kg doses given on day 2 and on day 7 p.i., or as a single injection of 50 mg/kg on day 2. The single 50 mg/kg dose was also effective when treatment was delayed until four days p.i., but was ineffective when treatment was delayed until six days p.i. The 50 mg/kg dose was not effective when given orally by gavage. No evidence of toxicity was noted in daily clinical examinations, or in frequent hematology and clinical chemistry tests performed during the clinical evaluation of the infection.
African Green monkeys were injected (2 x daily subcutaneously for six months) with human GRF(1-44)-NH2 (10 micrograms/kg BW) or a more potent analog, [desNH2Tyr1,Ala15]-hGRF(1-29)-NH2 (2 micrograms/kg BW) to determine the potential of each peptide to induce antibody formation. Blood samples were taken every two weeks, diluted 1:100 and tested for ability to bind radioiodinated hGRF. One animal in the hGRF(1-44)-NH2 group [N = 6] produced low-titer GRF antibodies by 6 weeks (19% binding) and continued throughout the 24 weeks of treatment (average = 50-60% binding). Similarly, one animal in the hGRF analog group [N = 6] displayed low-titer GRF antibodies by 18 weeks (14% binding), with the highest binding observed at 24 weeks (51% binding). Subsequent dilutions (1:1,000 and 1:3,000) of these bleedings confirmed that higher GRF antibody titers were not masked by antibody excess. Dialyzed sera from these two animals did not affect the abilities of hGRF(1-44)-NH2 or [desNH2Tyr1,Ala15]-hGRF(1-29)-NH2 to stimulate GH secretion by rat pituitary cells in vitro. After 20 weeks of treatment, significant GH responses (increased mean GH area under the curve 2.3-2.5 fold and GH peak 3.5-3.7 fold, that of control) were observed following hGRF or hGRF analog injection. Therefore, the low titer GRF antibodies detected in monkey sera during six months of treatment with hGRF or a potent analog were biologically non-neutralizing.
Necropsy reports from 28 rhesus monkeys that had been experimentally infected with simian immunodeficiency virus (SIV) and that were free of cytomegalovirus were reviewed. Lung sections from 24 of these monkeys that had no etiologic agent other than SIV detected in the lung were studied in detail by histopathologic, immunohistochemical, and electron microscopic examination and by in situ hybridization. Fourteen of the monkeys were part of a serial euthanasia study, while others were euthanatized after they became moribund. The following lesions were detected: perivascular inflammation, vasculitis, interstitial pneumonia, syncytial cells, hemorrhage, fibrin exudation, and pleural fibrosis. Perivascular inflammation was the most frequent lesion and occurred as early as 2 weeks after inoculation. Severe pneumonia and numerous syncytial cells were seen only in animals euthanatized because they had become moribund. The lesions appeared to be directly due to SIV infection. SIV antigens, RNA, and virions were detected in syncytial cells and macrophages by immunohistochemical examination, in situ hybridization, and transmission electron microscopic examination, respectively. The amount of virus present was correlated with the severity of the lesions. The SIV-induced lesions were different from those of the lymphocytic interstitial pneumonia, which occurs in human immunodeficiency virus-infected children and in ovine lentivirus-infected sheep and goats.
Six African green monkeys (six eyes) underwent vitrectomy and vitreous replacement with Vitreon (perfluorophenanthrene) or Vitreon plus silicone. A seventh animal served as a control. Vitreon alone and in combination remained optically clear and allowed fundus examination up to 162 days. No toxic effects to the retina were detectable. Vitreon exhibited some degree of emulsification and formed some globules at 45 days postoperatively. Interestingly, Vitreon emulsification occurred at a later time (80 days) in one of the silicone plus Vitreon eyes. The combination of silicone plus Vitreon may offer the advantage of tamponading the inferior and superior retina in phakic eyes.
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1-(2-Deoxy-2-fluoro-1-beta-D-arabinofuranosyl)-5-ethyluracil (FEAU) has been shown to be a highly effective inhibitor of Simian varicella virus infection in African green monkeys. Administration of FEAU by either intravenous injection or gavage at doses as low as 1 mg/kg/day prevented the development of rash and reduced viremia. The effective dose could be further reduced to 0.2 mg/kg/day when administered in combination with a sub-effective dose of human recombinant interferon-beta. No evidence of toxicity was seen in monkeys treated for 10 days with FEAU doses of 10 mg/kg/day when they were monitored by hematology and clinical chemistry tests and by clinical observations.
The management of opportunistic infections is a significant problem in acquired immunodeficiency syndrome (AIDS) and the development of more effective chemotherapeutic agents is needed. We present the ocular manifestations of an AIDS-like disease in rhesus monkeys experimentally infected with simian immunodeficiency virus (SIV) at the Delta Regional Primate Research Center. These findings consisted of rubeosis in the anterior segment and retinitis, optic neuritis, choroiditis and panophthalmitis in the posterior segment of the eye. Investigation of the retinas by electron microscopy revealed SIV in both eyes of one animal and a herpes virus in two animals. Serology confirmed cytomegalovirus (CMV) as the likely agent. This primate model will prove useful for both further investigations of the possible interaction between immunosuppressive lentiviruses and CMV in ocular disease and antiviral drug testing.
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Liposomal formulations (distearoylphosphatidylcholine:dipalmitoylphosphatidylglycerol, 9:1) of recombinant human interferon-beta ser17 (IFN-beta), administered im to African green monkeys at doses of 10(7) units/kg on days 1 and 6 after infection with simian varicella virus, resulted in partial protection of the monkeys from viral infection. Aqueous interferon administered under the same dosing regimen was ineffective. When given at 10(6) units/kg per dose twice daily for 10 d, however, it was highly effective in reducing viremia and rash. The antiviral efficacy obtained with the liposomal IFN-beta formulation given in two injections 5 d apart was thus significantly more efficacious than aqueous IFN-beta given in the same dosing regimen. However, it was not as efficacious as repeated, twice-daily injections of aqueous IFN-beta. Thus, im-injected liposomal IFN-beta, which results in sustained release of the IFN-beta from the injection site, exerts antiviral efficacy in a primate model superior to that obtained with the identical dosing regimen of aqueous IFN-beta.