Animal models of human immunodeficiency virus infection. Public Health Service Animal Models Committee.

The search for a model of HIV infection continues. While much of the initial work focussed on animal models of AIDS, more recent efforts have sought animal models of HIV infection in which one or more signs of AIDS may be reproduced. Most initial small animal modelling efforts were negative and many such efforts remain unpublished. In 1988, the Public Health Service (PHS) AIDS Animal Model Committee conducted a survey among PHS agencies to identify published and unpublished data on animal models of HIV. To date, the chimpanzee is the only animal to be reliably infected with HIV albeit without development of signs and symptoms normally associated with human AIDS. One recent study has shown the gibbon to be similarly susceptible to infection with HIV. Mice carrying a chimera of elements of the human immune system have been shown to support the growth of HIV and F1 progeny of transgenic mice containing intact copies of HIV proviral DNA, have developed a disease that resembles some aspects of human AIDS. Rabbits, baboons and rhesus monkeys have also been shown to be infected under certain conditions and/or with selected strains of HIV but again without the development of AIDS symptomatology. This report briefly summarizes published and available unpublished data on these efforts to develop an animal model of HIV infection.

Protective and toxic effects of a nuclease-resistant derivative of polyriboinosinic-polyribocytidylic acid on Venezuelan equine encephalomyelitis virus in rhesus monkeys.

Polyriboinosinic-polyribocytidylic acid, stabilized with poly-L-lysine and carboxymethylcellulose (poly ICLC), favorably alters the pathogenesis of Venezuelan equine encephalomyelitis virus infection in rhesus monkeys by decreasing the number of infected monkey that become detectably viremic and by delaying the onset of viremia in the remaining monkeys. Poly ICLC is known to induce high circulating levels of interferon in primates, and the interferon system is assumed to be the mechanism by which poly ICLC exerts its antiviral effect. Poly ICLC treatment was associated with a few deaths, but only under certain conditions of infection and handling. The death of some infected, treated monkeys in the absence of death in monkeys that were either infected and untreated or treated and uninfected suggests a synergistic toxicity resulting from the combination of infection, handling, and poly ICLC treatment, although other explanations are possible.

Studies of the coagulation system and blood pressure during experimental Bolivian hemorrhagic fever in rhesus monkeys.

Experimental infection of rhesus monkeys (Macaca mulatta) with Machupo virus produced a hemorrhagic disease similar to that of Bolivian hemorrhagic fever in humans. The disease in infected animals was also characterized by the development of hypotension and coagulation abnormalities as indicated by severe thrombocytopenia and prolongation of the activated partial thromboplastin time. Evidence for disseminated intravascular coagulation was inconclusive due to the presence of normal to elevated fibrinogen levels, relatively low levels of circulating fibrin split products, and the lack of widespread fibrin thrombus deposition. The most likely causes of the hemorrhagic tendencies of this disease in infected monkeys were thrombocytopenia and decreased synthesis of coagulation and other plasma proteins due to severe hepatocellular necrosis. Hypotension may also have been due to decreased plasma protein synthesis.

Effect of a nuclease-resistant derivative of polyriboinosinic-polyribocytidylic acid complex on yellow fever in rhesus monkeys (Macaca mulatta).

Rhesus monkeys (Macaca mulatta) treated with a newly developed nuclease-resistant complex of polyriboinosinic-polyribocytidylic acid, poly-L-lysine, and carboxymethylcellulose [poly (ICLC)] did not die after challenge with virulent Asibi strain yellow fever (YF) virus. The strain of virus is sensitive to the effects of interferon in vitro and is lethal for rhesus monkeys four to six days after subcutaneous administration of 1,000 plaque-forming units of the virus. The mortality rate was reduced in monkeys initially treated 8 hr before or after inoculation of virus but was unchanged in monkeys initially treated 24 hr after challenge. Treated monkeys developed neutralizing antibody to YF virus. The successful treatment of yellow fever in a primate model with use of poly (ICLC) suggests a meaningful role for the interferon system in the host defense against this viral infection.

Inactivated Venezuelan equine encephalomyelitis virus vaccine complexed with specific antibody: enhanced primary immune response and altered pattern of antibody class elicited.

Complexes of formalinized Venezuelan equine encephalomyelitis (VEE) virus vaccine and specific IgG formed at antigen-antibody equivalence enhanced the immune responses of rhesus monkeys (Macaca mulatta). The predomonant class of antibody elicited by complexes was IgG. In contrast, lower titers of antibody and a more biphasic (IgG-IgM) response were observed after exposure of monkeys to the vaccine alone. In comparison to the response of monkeys primed with antigen, a more rapid secondary response was obtained in monkeys primed with the complexes of antigen and antibody formed at equivalence. A sustained level of protection of 88% was afforded mice 24 hr after immunization with antigen-antibody complexes; development of protection after administration of antigen required eight days to reach this level. Passive protection (80%-100%) was conferred by IgG controls for seven to eight days after immunization. This level of protection was not significantly affected by X-irradiation 24 hr prior to administration of IgG; however, protection in mice similarly irradiated prior to immunization with antigen-antibody complexes was significantly decreased. Early protection afforded by the complexes was not nonspecific (interferon) but was mediated by specific immunologic mechanisms and may be caused by an early formation of IgG.

Changes in blood serum constituents and hematologic values in Macaca mulatta with Rocky Mountain spotted fever.

Forty-seven male Macaca mulatta, 3 to 4 kg weight, were inoculated intravenously or subcutaneously with various doses of yolk sac-grown Rickettsia rickettsii. Thirty-four macaques became febrile and exhibited signs of infection ranging from transient illness with a few days of fever to severe illness with subsequent death. The rash appeared more frequently in the macaques inoculated subcutaneously. Febrile macaques that survived had leukocytosis, with concomitant neutrophilia. Febrile macaques that died had, in addition, marked terminal leukopenia and thrombocytopenia. Packed cell volume of all febrile macaques decreased. In almost all of the febrile macaques, there were increased serum urea nitrogen, glutamic-oxaloacetic transaminase, and lactate dehydrogenase and decreased total serum protein and amylase concentrations. A few febrile macaques had increased bilirubin values and decreased sodium, chloride, phosphorus, and alkaline phosphatase concentrations. Changes did not occur in serum glucose, potassium, calcium, and glutamic-pyruvic transaminase values. The experimental form of Rocky Mountain spotted fever in the macaque provides a subhuman primate model for studying the pathophysiology of this disease.

Small-particle aerosols of antiviral compounds in treatment of type A influenza pneumonia in mice.

Three chemotherapeutic drugs active against type A influenza virus (amantadine, rimantadine, and ribavirin) were tested as therapeutic agents against established infections with influenza virus in mice. The drugs were administered intraperitoneally or as aerosols either from 6 hr to four days or from three to seven days after infection. Small-particle aerosols were administered continuously 24 hr per day. Continuous dissemination of aerosols was superior to intraperitoneal administration, as evidenced by higher survival rates at 21 days. Rimantadine, amantadine, and ribavirin were effective when treatment was delayed for three days. Ribavirin was the most efficacious if therapy was initiated as an aerosol 6 hr after infection. In contrast to amantadine, ribavirin given in samll-particle aerosols at 6 hr prevented the development of pneumonia and decreased titers of virus in lung.

Response of sublethally irradiated monkeys to a replicating viral antigen.

Temporal effects of exposure to sublethal, total-body X radiation (400 R) on responses to vaccination with attenuated Venezuelan equine encephalomyelitis vaccine virus. TC-83, were examined in rhesus monkeys. Viremia, often with delayed onset, was prolonged even when irradiation preceded vaccination by 28 days. Virus titers were increased, articularly in groups irradiated 4 or 7 days before vaccination. Delay in appearance of hemagglutination-inhibition and serum-neutralizing antibody correlated closely with persistence of viremia in irradiated-vaccinated monkeys. The temporal course of antibody response was markedly affected by the intervals between irradiation and injection of this replicating antigen. With longer intervals between irradiation and vaccination, the somewhat depressed antibody responses approached normal or surpassed those of nonirradiated monkeys. Vaccination 14 days after radiation exposure resulted in lethality to 8 of 12 monkeys, apparently as a result of secondary infection. The additional lymphopenic stress due to the effect of TC-83, superimposed on the severly depressed hematopoietic competence at 14 days, undoubtedly contributed to this increased susceptibility to latent infection.

Treatment of influenza infection of mice by using rimantadine hydrochlorides by the aerosol and intraperitoneal routes.

Rimantadine hydrochloride was administered for 4 days in a small-particle (95% < 6.5 mum) 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.

Response of irradiated mice to live-virus (TC-83) immunization.

Studies were conducted to determine the effects of sublethal, acute, total-body irradiation (600 R) on the immune response of mice to a replicating antigen. Irradiation was performed at varying times (0 to 21 days) prior to immunization with attenuated Venezuelan equine encephalomyelitis virus, TC-83. Development of protective immunity was studied by inoculating subgroups of irradiated mice with virulent Venezuelan equine encephalomyelitis virus on days 1 through 28 after immunization. Irradiation failed to affect the overt clinical response of mice inoculated with the attenuated strain, but antibody responses and the onset of protective immunity was delayed, particularly in mice irradiated 2 h to 3 days prior to vaccination. Immunity afforded by TC-83 developed more rapidly as the interval between irradiation and vaccination increased: when this interval was 14 or more days, the temporal course of immune response in irradiated mice was similar to that of nonirradiated vaccines. Persistence of TC-83 viremia was greatly prolonged in irradiated mice through the irradiation recovery period and probably provided the antigenic stimulus responsible for delayed development of effective immunity.

Mechanisms of oral staphylococcal enterotoxin B-induced emesis in the monkey (38553).

Vomition is the most consistent response to oral SEB challenge in the monkey. The technique of cross-circulation clearly differentiates local neural phenomenon from humoral mechanisms. Our results support the theory that SED-induced vomition follows stimulation of local neural receptors in the gut. The evidence indicates no significant amount of enterotoxin absorption or stimulation of vomition by any centrally acting humoral mechanism.

Effects of antigen-antibody complexes on the primary immune response in Rhesus monkeys.

A model for the enhancement of the primary humoral immune response of rhesus monkeys to marginal or weakly antigenic vaccines is presented. Our procedure used the complexing of formalin-inactivated Venezuelan equine encephalomyelitis (VEE) virus vaccine with specific, homologous, immune gamma globulin (IgG) at equivalence. Equivalence was determined by combining the concentrated, isotopically labeled ((3)H) virus with various concentrations of specific Sephadex-fractionated IgG. Enhancement of VEE virus antibody response in monkeys was obtained from preparations containing a marginal concentration of antigen that was complexed at equivalence with homologous IgG as compared with antigen alone. Protection in Swiss mice closely paralleled the antibody response pattern observed in monkeys, since complexes at equivalence provided 30 to 50% greater protection against challenge than antigen alone.

Yellow fever vaccine: direct challenge of monkeys given graded doses of 17D vaccine.

In rhesus monkeys a wide dosage range of 17D yellow fever (YF) vaccine extending to a level even below that recommended for vaccination of man elicited an immune response providing solid protection to challenge with virulent YF virus. Forty-three of 45 monkeys vaccinated with 10(2.3) or greater weanling mouse mean lethal doses of 17D vaccine were resistant to challenge 20 weeks later with virulent Asibi strain YF virus. Monkeys given graded doses of lesser amounts of vaccine were progressively more susceptible to challenge. With a vaccine dose >/= 10(2.3) weanling mouse mean lethal doses, plaque neutralization (PN) seroconversion rates were 90% or greater, whereas hemagglutination-inhibiting (HI) and complement-fixing (CF) seroconversion rates were unrelated to vaccine dosage and were generally in the range of 20 to 80%. Ninety-six percent (51 of 54) of immune monkeys had PN titers >/=0.7 log(10) (fivefold) neutralization index as compared to approximately 55 to 65% who showed HI or CF titers >/=2 log(2) (fourfold) neutralization index. After challenge with Asibi strain YF virus, antibody titers of all three tests increaed equally. In rhesus monkeys PN antibody titers were well correlated with YF immunity, whereas HI and CF antibody titers were not.