A model for studying the pathogenesis of virulent arenavirus infection was developed by adapting Pichinde virus to produce lethal infections of inbred guinea pigs. This adapted Pichinde virus retained low virulence for primates, thus potentially reducing the biohazard to investigators. Whereas all inbred (strain 13) guinea pigs were infected and killed by 3 plaque-forming units or more of adapted Pichinde virus injected subcutaneously, outbred (Hartley strain) guinea pigs were relatively resistant. All infected, inbred guinea pigs died at 13 to 19 days after inoculation, with viremias in excess of 5 log 10 plaque-forming units/ml, severe lymphopenia (<1,000/mm 3 ), and elevated serum glutamic oxaloacetic acid transaminase levels. Immunofluorescent antibody examination of tissues and infectivity titrations of tissue homogenates obtained at 3- to 4-day intervals demonstrated significant viral replication in all visceral tissues examined, but not in brain. Livers of all moribund guinea pigs contained moderate to severe hepatocellular necrosis and diffuse fatty change. Splenic red pulp and adrenal cortical tissues were engorged with blood and contained necrotic foci. Pancreatic acinar tissues were atrophied and vacuolated; lung sections typically contained areas of moderate to severe interstitial pneumonia. Inflammatory cells were conspicuously absent from all lesions. The virological and pathological features of adapted Pichinde infection in guinea pigs are remarkably similar to those described for Lassa virus infections in rhesus monkeys and humans, suggesting that this model might provide insight into the pathogenesis and treatment of Lassa fever in humans.

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A plaque assay for Ebola virus is reported. The procedure has real potential for future research, although it is less sensitive than indirect fluorescent-antibody and mouse inoculation tests.

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Endoscopic, histologie, and microbiologie evaluations of 21 cynomolgus and 34 rhesus monkeys for naturally occurring Helicobacter pylori infection were done. H. pylori was never isolated from any cynomolgus monkey, but was found in 12 rhesus monkeys. A general correlation existed between a positive culture and a gastric inflammatory response. Inoculation challenges were then undertaken. Four cynomolgus and five rhesus monkeys received two different H. pylori strains isolated from humans. Five rhesus monkeys received an isolate obtained from rhesus monkeys. Evaluation of the cynomolgus monkeys 7 and 14 days later revealed no H. pylori. Endoscopies of the rhesus monkeys were done 7, 14, 21, 28, and 56 days later. One rhesus monkey, which received the isolate from humans, became H. pylori positive at day 21 and remained positive through day 56. Restriction enzyme analysis of genomic DNA at day 56 revealed that the isolate was not identical to the challenge strain isolated from humans. All five rhesus monkeys that received the strain isolated from rhesus monkeys became H. pylori positive by day 14 and remained positive through day 56. Antral inflammation developed in all monkeys. Restriction enzyme analysis of genomic DNA on day 56 confirmed that four of five isolates were identical to the challenge strain isolated from rhesus monkeys. DNA hybridization documented homology between the challenge strains isolated from humans and rhesus monkeys plus those isolated at day 56. In this study, we showed that the rhesus monkey, if given a strain ofH. pylori isolated from rhesus monkeys, develops a gastric infection with accompanying histological changes, making this model suitable for further development.

Ribavirin (1-,8--ribofuranosyl-1,2,4-triazole-3-carboxamide) is an effective antiviral agent against type A influenza infection of mice. Therapy was most effective when administered as a small-particle aerosol early in the infection. Treatment was also effective by either the intraperitoneal or aerosol route in mice with histological evidence of pneumonia. Ribavirin increased the percent survival, lowered lung virus titers, and decreased the development of lung pathology when therapy was initiated at 6 h as a small-particle aerosol. There was no evidence of pulmonary toxicity or immunosuppressive effects.Virus diseases of man and animals represent an important group of disease entities. Notwithstanding the influenza pandemic of 1918 to 1919, which was accompanied by great loss of life, influenza, like most virus diseases, is usually self-limiting and not associated with high mortality unless complicated by bacterial pneumonia. In 1957, Horsfall estimated that man suffers with viral diseases for 7 years of a 70-year life span (5). Loosli has stated that influenza is the major incapacitating viral disease not adequately controlled by vaccines (9).Ribavirin has antiviral activity against both ribonucleic and deoxyribonucleic acid viruses (6,13,17). The demonstration that small-particle aerosols containing rimantadine or amantadine-hydrochloride were effective for the treatment of influenza virus-infected mice (15,16) and the reported efficacy of parenterally injected ribavirin against lethal influenza infections in mice (1, 7) suggested that aerosols of ribavirin might be useful for the treatment of influenza. This report describes the therapeutic efficacy of ribavirin given in small-particle aerosols to treat experimental influenza virus infection in mice.MATERIALS AND METHODS Mice. Five-week-old outbred, female mice, Tac:(SW)fBR, were used for all experiments. Upon arrival, mice were housed 15 to a cage in random order. Each group of mice contained a separate subgroup destined for the same treatment, but reserved for serial sacrifice studies in addition to those recorded for survival. Groups contained 55 mice except that continuously treated groups contained 40 mice.Virus. The mouse-adapted variant of the A/Aichi/ 2/68 (H3N2) strain of influenza virus used to infect the mice has been previously described (12, 15).Lung virus titers. Lung samples were homogenized in 4.5 ml of heart infusion broth and assayed in 10-to 12-day-old embryonated eggs (15). Lung titers, expressed as the mean egg infective dose per lung, are the geometric mean of three individual mouse lungs at the indicated times postexposure. When no virus was detected in a lung sample, a value of 1.0 was assigned to calculate the geometric mean titer.Aerosol sampling and dissemination system. The dissemination system used to infect the mice and for intermittent therapy has been previously described (15). The aerosols for continuous therapy were generated by a modified Collison system developed in our laboratory. The particles generated by this system h...

Rimantadine hydrochloride was administered for 4 days in a small-particle (95% < 6.5 μm) aerosol (8.8 mg/kg per day) or intraperitoneally (40 mg/kg per day) to mice previously infected with influenza A/Aichi/2/68 (H 3 N 2 ), mouse adapted. Mean time to death and incidence of survival were significantly increased in all treated groups of mice. The rate of eventual disappearance of virus from lung tissue was also accelerated by therapy. However, maximal mean virus titer per lung, and lung histopathology, did not reveal any difference between control and either group of treated mice. Aerosol therapy initiated at 72 h postinfection was as effective as that initiated at 6 h, even though lung virus titers of these mice had already peaked by 72 h. In contrast, intraperitoneal therapy initiated at 72 h was not effective in all studies.

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