Enhancement of simian varicella virus infection in African green monkeys by recombinant human tumor necrosis factor alpha.
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Animals↗
Biomedical subjects
K F Soike
Publications and source records attributed to K F Soike.
Liposomal interferon-beta: sustained release treatment of simian varicella virus infection in monkeys.
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.
Animals↗
Adenovirus enteritis in SIV-infected rhesus monkeys.
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Adenoviridae Infections↗
Serological survey for viral diseases in the Cayo Santiago rhesus macaque population.
The free-ranging population of rhesus monkeys (Macaca mulatta) on Cayo Santiago was sero-surveyed for human measles, simian virus 40, B virus (Herpes simiae), rhesus cytomegalovirus, human and simian retroviruses and encephalomyocarditis virus to determine the prevalence of these viruses in the colony. The results of this study indicate that the colony is free of SV40, HTLVIII (HIV-1), STLVIII (SIV) and SRV1; has a low prevalence of measles and EMCV; and high prevalence rates for B virus, CMV and HTLVI.
Academies and Institutes↗
Pharmacokinetics of human recombinant interferon-alpha I after i.v. infusion and im injection in African green monkeys.
The pharmacokinetics of recombinant human interferon-alpha I (rHuIFN-alphaI) were studied following a single 3 X 10(6) U/kg dose administered as a 30-min intravenous (iv) infusion and as an intramuscular (im) injection to four African green monkeys using a crossover design. Concentrations of rHuIFN-alpha I in serum were determined by bioassay. Serum rHuIFN-alpha I concentrations declined rapidly following an iv infusion. The elimination half-life ranged from 1.7 to 2.0 h. The volume of distribution at steady state and the total body clearance ranged from 0.42 to 2.4 L/kg and 28 to 233 ml/min, respectively. A protracted absorption profile was seen following im injection, with a highly variable bioavailability ranging from 16 to 680%, compared with the iv infusion. The overall disposition of rHuIFN-alpha I is comparable to that of rHuIFN-alpha A and other IFNs in monkeys.
Animals↗
Pharmacokinetics and antiviral activity in simian varicella virus-infected monkeys of (R,S)-9-[4-hydroxy-2-(hydroxymethyl) butyl]guanine, an anti-varicella-zoster virus drug.
The acyclic guanosine analog (R,S)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine, (+/-)2HM-HBG, is an effective inhibitor of herpes simplex virus and varicella-zoster virus infections in vitro. This report is concerned with the pharmacokinetic evaluation of the drug in rats and monkeys and its antiviral activity in African green monkeys infected with simian varicella virus (SVV), a virus closely related to varicella-zoster virus that is also susceptible to inhibition by (+/-)2HM-HBG. Elimination half-lives in plasma following intravenous administration to monkeys (100 mumol/kg of body weight) ranged from 1.8 to 2.2 h, and total body clearance was 9.0 +/- 0.4 ml/min per kg (mean +/- standard error). After oral administration, levels in plasma were low, with a maximum concentration of the drug of only 3.1 +/- 0.8 microM, a time to reach maximum concentration of drug of 2.7 +/- 0.4 h, and an oral bioavailability of 10.6 +/- 1.4%. Because of the low oral bioavailability, SVV-infected monkeys were treated intramuscularly with (+/-)2HM-HBG. (+/-)2HM-HBG at a dosage of 10 mg/kg of body weight per day allowed moderate viremia, whereas a dosage of 30 mg/kg of body weight per day strongly suppressed viremia with minimal numbers of virus plaques from blood specimens collected at days 3, 5, and 7 postinfection and complete clearance at day 9 postinfection. Titers of antibody to SVV were also low. Treatment three times daily was somewhat more efficacious than treatment twice daily. Thus, (+/-)2HM-HBG is an effective inhibitor of SVV replication in vivo, despite the fact that leves of (+/-)2HM-HBG in plasma were low at extended periods of time and below the concentration of drug giving 50% inhibition of plaque formation obtained in vitro.
Administration, Oral↗
Immunization of monkeys with varicella-zoster virus glycoprotein antigens and their response to challenge with simian varicella virus.
African green monkeys (Cercopithecus aethiops) were immunized with three intramuscular injections of gpI, gpII, or gpIII glycoprotein antigens of varicella-zoster virus (VZV). Antibody responses to VZV were determined by enzyme-linked immunosorbent assay (ELISA) and to simian varicella virus (SVV) by immunofluorescence and by serum neutralization assays. Two weeks following the third immunization with VZV glycoproteins, the monkeys were challenged by inoculation of SVV. Antibodies to gpII or gpIII partially prevented infection by SVV, while the presence of antibodies to gpI was ineffective in preventing disease induced by SVV challenge. Factors affecting the immunogenicity of these antigens in this model are discussed.
Animals↗
Effect of 9-(1,3-dihydroxy-2-propoxymethyl)guanine and recombinant human beta interferon alone and in combination on simian varicella virus infection in monkeys.
Treatment of viral infections with combinations of antiviral agents may permit administration of reduced doses of either or both drugs. Lowered doses may reduce associated toxicity. Intravenous administration of substantial doses of either human recombinant beta interferon (rHuIFN-beta) or 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG) prevents development of simian varicella virus infection in African green monkeys. Daily doses of 2 X 10(6) U of rHuIFN-beta/kg inhibited clinical disease in monkeys inoculated with simian varicella virus, and doses of DHPG between 20 and 60 mg/kg per day were necessary for similar antiviral effects. Intravenous administration of combinations of rHuIFN-beta and DHPG permitted an approximately 100-fold reduction in the effective dose of rHuIFN-beta and a 10-fold reduction in the effective dose of DHPG. Analysis of data relating to viremia by using the method of the median-effect principle showed the combination of rHuIFN-beta and DHPG was strongly synergistic in treatment of this infection.
Acyclovir↗
Activity of 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-iodouracil against simian varicella virus infections in African green monkeys.
The fluorinated pyrimidines 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-iodouracil (FIAU) and 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-methyluracil (FMAU) are highly effective inhibitors of herpesvirus infections in vitro and in vivo. This report is concerned with an evaluation of their activities in African green monkeys (Cercopithecus aethiops) infected with simian varicella virus, a herpesvirus closely related to human varicella-zoster virus. Oral or intravenous administration of FIAU at 50 mg/kg per day as divided doses beginning 48 h after virus inoculation prevented the development of evidences of clinical infection. Oral treatment with FIAU at 30 mg/kg per day deferred as late as 7 days after virus inoculation modified the course of the disease. When treatment was started 48 h after virus inoculation, daily doses of FIAU as small as 1 mg/kg inhibited development of infections; daily doses of 0.2 mg/kg were ineffective. At the latter dose FMAU prevented development of clinical disease, suggesting that it was more active than FIAU. No signs of FIAU toxicity were observed, with the single exception of an early but transitory elevation in aspartate aminotransferase activity in serum.
Administration, Oral↗
Transmissible lymphoma and simian acquired immunodeficiency syndrome in rhesus monkeys.
Four rhesus monkeys (Macaca mulatta) were inoculated with a homogenate of a cutaneous lepromatous leprosy lesion from a mangabey monkey (Cercocebus atys). One died of B-cell lymphoma, and another died of an immunodeficiency syndrome. Cell suspensions prepared from the tumor and spleen of the monkey with lymphoma induced lymphoma or an immunodeficiency syndrome when inoculated into additional young rhesus monkeys. The immunodeficiency syndrome was similar to simian acquired immunodeficiency syndrome and consisted of opportunistic infections, lymphoid hyperplasia or atrophy, wasting, and syncytial cell formation. Mitogen responses and percentages of T4- and T8-positive lymphocytes were normal until the animals were moribund. Lymphoblastoid cell lines became established in vitro from tumor cell suspensions. These cells were infected with a herpesvirus related to Epstein-Barr virus. In addition, a retrovirus morphologically similar to human T-cell lymphotrophic virus type III (HTLV-III) and simian T-lymphotrophic virus type III (STLV-III) was isolated from one of the lymphoblastoid cell lines (LCL). Type D retroviruses could not be demonstrated in the monkeys in the transmission study; however, a retrovirus similar to that in the LCL was isolated from 4 animals by coculture of peripheral blood lymphocytes with the human cell line H9. These results suggest that this retrovirus, STLV-III/Delta, may be associated with the immunodeficiency syndrome in these macaques and may be of mangabey origin.
Acquired Immunodeficiency Syndrome↗
Coxsackievirus B4 infection of sympathetic ganglia in squirrel monkeys.
Lumbar sympathetic ganglionitis was found by light microscopy in 2 of 17 (12%) squirrel monkeys (Saimiri sciureus) experimentally infected with Coxsackievirus B4. This finding shows that viruses can cause ganglionitis which, in turn, must cause autonomic nervous system dysfunction. Such viral ganglionitis may explain some diseases, including cardiovascular ones, of poorly understood or unknown etiology which present with manifestations of dysfunction of the sympathetic nervous system.
Animals↗
Experimental coxsackievirus B4 meningitis.
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Animals↗
Investigation of antiviral activity of 1-beta-D-arabinofuranosylthymine (ara-T) and 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil (BV-ara-U) in monkeys infected with simian varicella virus.
1-beta-D-Arabinofuranosylthymine (ara-T) and 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil (BV-ara-U) were shown to have antiviral activity in vitro and in vivo against simian varicella virus. Both compounds successfully prevented clinical disease caused by inoculation of African green monkeys with simian varicella virus, eliminating the development of rash and substantially suppressing viremia. Ara-T treatment was effective by either intraperitoneal or oral routes of administration and BV-ara-U was active by both oral and intramuscular routes. Ara-T, however, was associated with the appearance of marked signs of neurotoxicity. Histologic examination of brain tissue demonstrated chromatolysis and pyknosis of neurons and pyknotic nuclei in glial cells. The neurologic impairment persisted in affected monkeys. This observation of central nervous system toxicity in monkeys is in contrast to studies in mice and rats where high doses of ara-T by multiple routes of administration were nontoxic. No apparent toxicity was observed in monkeys treated with BV-ara-U.
Animals↗
Viral disease models in primates.
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Animals↗
Pharmacokinetics of recombinant alpha A interferon following I.V. infusion and bolus, I.M., and P.O. administrations to African green monkeys.
The pharmacokinetics of recombinant alpha A interferon (rIFN-alpha A) were studied following an intravenous (iv) bolus, 60 min infusion, intramuscular (im), and oral administrations to four African Green monkeys. Each monkey received 3 X 10(6) units/kg of rIFN-alpha A parenterally and 6 X 10(6) units/kg orally. Blood samples were collected and the serum was separated and analyzed for rIFN-alpha A concentrations by an enzyme immunoassay, ELISA. No significant changes in clinical chemistry values resulted from rIFN-alpha A administration. There were no measurable rIFN-alpha A concentrations (less than 20 pg/ml) following oral administration. Serum rIFN-alpha A concentrations declined rapidly in a biphasic manner following iv bolus and infusion doses and were described by a single pharmacokinetic model. The volume of distribution at steady state (Vdss) ranged from 0.034 to 0.31 l/kg after iv infusion. Total clearance ranged from 4.5 to 19 ml/min, which is about 75% the estimated inulin clearance in monkeys, suggesting glomerular filtration without reabsorption. The elimination half-life ranged from 1.8 to 4.8 h. A prolonged absorption profile was seen following im administration and the systemic bioavailability was 93% when compared with intravenous infusion. The overall disposition of rIFN-alpha A is comparable to the disposition of other interferons in both animals and humans. The monkey appears to be a suitable pharmacokinetic model for the testing of rIFN-alpha A and could be useful in conjunction with a viral efficacy model.
Administration, Oral↗
In vivo antiviral activity of recombinant type alpha interferon A in monkeys with infections due to simian varicella virus.
Recombinant type alpha interferon A (rIFN-alpha-A) administered to African green monkeys (Cercopithecus aethiops) intramuscularly in a dose of 3 X 10(6) units/kg of body weight resulted in substantial blood levels of interferon. Peak levels of greater than 1,000 units/ml of serum appeared at 1 and 2 hr after inoculation and interferon was detectable for as long as 12 hr after inoculation. Injection of rIFN-alpha-A at a dose of 10(6) units/kg twice daily for eight days effectively inhibited simian varicella virus infection of the African green monkey. Antiviral activity was demonstrated in monkeys with prophylactic treatment begun 4 hr prior to virus inoculation or with therapeutic treatment deferred until 44 hr after virus inoculation. No adverse effects of treatment were observed.
Animals↗
Coxsackievirus B4 hepatitis in monkeys.
Hepatitis was produced by Coxsackievirus B4, an agent highly infectious to man, in 3 of 9 experimentally infected squirrel monkeys. Although the virus could not be isolated from the livers of these monkeys, viral antigen was found in the liver cells of one monkey with severe hepatitis by direct immunofluorescent antibody staining, and a virus crystal was found in the kidney of this monkey by electron microscopy. These and previous studies strongly suggest that the Coxsackievirus can exist in the liver and other tissues in a dormant or slow viral state.
Animals↗
Activation and antiviral effect of acyclovir in cells infected with a varicella-like simian virus.
Acyclovir inhibited the replication of a varicella-like simian virus (DHV-1) in cell culture (Vero cells) with an ED50 of 38 +/- 2 microM. The activation of acyclovir in this cell culture system was compared with that in the cell system with human varicella zoster virus (VZV). Extracts of cells infected with DHV-1 catalyzed the phosphorylation of acyclovir. The phosphorylation was inhibited by dThd, suggesting the catalyst was a dThd kinase. Electrophoresis of cytosol fractions on polyacrylamide gels corroborated the existence of a virus-associated dThd kinase. This enzyme copurified with an acyclovir-phosphorylating activity. The enzyme catalyzed the phosphorylation of acyclovir at a greater relative rate than that with the VZV enzyme, but with a higher apparent Km value for acyclovir. The relative efficiencies for the two enzymes with acyclovir were similar. Anabolic studies with cells infected with DHV-1 and incubated with [14C]acyclovir indicated that triphosphate of acyclovir did accumulate. The results indicate that acyclovir is activated in cells infected with DHV-1 in a manner similar to that in cells infected with VZV.
Acyclovir↗