Impaired responses to Mycobacterium leprae antigens in rhesus monkeys experimentally inoculated with simian immunodeficiency virus and M. leprae.

Seven of eight rhesus monkeys (RM) coinfected with simian immunodeficiency virus (SIV) and Mycobacterium leprae harboured acid-fast bacilli (AFB) at sites of dermal inoculation and/or at disseminated sites at times of humane sacrifice (up to 270 days post-M. leprae inoculation) due to SIV-induced debilitation or, in one long term survivor's case, to date over 3 years post-M. leprae inoculation. Detectable AFB were cleared in biopsies of inoculation sites of RM inoculated with M. leprae alone after 63 days postinoculation; these sites have, so far, remained AFB-negative, thereafter. Compared to animals infected with M. leprae alone, RM coinfected with SIV plus M. leprae showed: 1, completely suppressed serum antibody responses to M. leprae-specific PGL-I antigen, but strong anti-SIV Gp120 antibody responses; 2, impaired sensitization of blood mononuclear cells (MNC) to in vitro recognition of M. leprae-specific antigens in blastogenic stimulation assays; 3, impaired in vitro responses of blood MNC to nonspecific (ConA) blastogenic stimuli; and 4, early post-M. leprae inoculation, there was a significant incremental diminution of percentages of blood CD4+CD29+ T-cells in addition to the existing SIV-induced diminished percentages of CD4+CD29+ T-cells. The results indicate that humoral and cellular immune responses to M. leprae antigens are compromised in M. leprae-inoculated RM previously infected with SIV. These results provide an immunologic basis for the demonstration of enhanced M. leprae persistence or leprosy susceptibility in SIV-M. leprae coinfected RM.

A second sooty mangabey monkey with naturally acquired leprosy: first reported possible monkey-to-monkey transmission.

The existence of naturally acquired leprosy in a second sooty mangabey monkey has been documented. The disease has the clinical and histopathological characteristics of subpolar lepromatous leprosy (LLs), and microbiological studies thus far confirm the etiologic agent as Mycobacterium leprae. This mangabey had been housed in direct contact with the first mangabey in which naturally acquired leprosy was diagnosed in 1979. Clinical symptoms appeared in the second mangabey in 1986, almost 7 years after the appearance of skin lesions in the first monkey. It is likely that the second mangabey contracted leprosy from the first mangabey or that both animals contracted the disease by contact with an unknown common third source. This is the only known possible natural transmission of leprosy from monkey to monkey, and suggests that a potential zoonosis exists in wild monkeys that may serve as a reservoir for the disease in areas where human leprosy is endemic.

Leprosy as a zoonosis: an update.

Naturally-acquired leprosy has been reported in nine-banded armadillos captured in the southern United States, a chimpanzee from Sierra Leone, and in two "sooty" mangabey monkeys from Nigeria. A significant prevalence of leprosy in wild armadillos establishes this animal as a reservoir of M. leprae, and exposure to armadillos has been implicated as a source of leprosy in humans. Current evidence suggests that leprosy is a zoonosis in certain nonhuman primate species. Control and eradication programs for leprosy should take into consideration the possible influence of extra-human sources of M. leprae, especially zoonotic leprosy.

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.

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.

Leprosy in a mangabey monkey--naturally acquired infection.

Naturally acquired leprosy was detected in an otherwise normal "sooty" mangabey monkey (Cercocebus atys). This animal was imported from West Africa in 1975 and developed clinical symptoms of leprosy in 1979. Histopathologic findings were those of subpolar-lepromatous to borderline-lepromatous leprosy in the Ridley-Jopling classification. The disease was progressive, with crippling neuropathic deformities of the hands and feet. The disease regressed under specific therapy. The etiologic agent was identified as Mycobacterium leprae by the following criteria: invasion of nerves of host, staining properties, electron microscopic findings, noncultivable on mycobacteriologic media, DOPA-oxidase positive, lepromin reactivity, infection patterns in mice and armadillos, sensitivity to sulfone, and DNA homology. We believe the animal acquired the disease from a patient with active leprosy. The mangabey monkey offers promise as a primate model for leprosy, and adds a third reported species to animals with naturally acquired leprosy.

Depression of lymphocyte responses to mitogens in mangabeys with disseminated experimental leprosy.

Mononuclear cells from mangabey monkeys with disseminated experimental leprosy had increasingly severe depression of blastogenic responses to phytohemagglutinin, concanavalin A, and pokeweed mitogen as the disease progressed. Blastogenic responses were not depressed in cells from mangabeys with more localized disease. Blastogenic responses of cells from normal mangabeys appeared to vary with a circannual rhythm. The demonstration of significant negative correlations between the blastogenic responses to mitogens and the percentages of OKT8+ cells suggested that the mangabey OKT8+ subset may contain cells with suppressor function. The depressed responses to mitogens by cells from monkeys with disseminated experimental leprosy were associated with relatively high percentages of OKT8+ cells. Polyclonal immunoglobulin plaque-forming cell responses to pokeweed mitogen were depressed in cells from experimentally infected mangabeys. The results indicated that defects in immune regulation may occur in experimental leprosy in mangabeys, similar in some respects to the defects that have been reported in human leprosy.

Electron microscopic study of leprosy in a mangabey monkey (natural infection).

Ultrastructural features of the leproma of a) a naturally infected mangabey monkey, and lepromas and liver of b) a passage mangabey monkey, c) a rhesus monkey, d) an African green monkey, and e) a nine-banded armadillo inoculated with leprosy bacilli isolated from the leproma of a naturally infected mangabey monkey were studied by the freeze-etching technique. The size, shape, and ultrastructural features of leprosy bacilli in the phagolysosomes of macrophages in all of these samples were essentially the same as those in humans, nude mice, and armadillos inoculated with human Mycobacterium leprae. Distinct accumulations of small spherical droplets were observed around leprosy bacilli inside lepra cells of all the samples but were scarce in the specimen from the green monkey. The bacilli in all samples were long and slender, and had band structures on the smooth cell wall surfaces. The bacilli were indistinguishable from M. leprae.

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.

Modelos de lepra multibacilar en huéspedes no alterados: estado actual / Multibacillary models of leprosy in not changed hosts: actual status

Se ha reportado lepra diseminada multibacilar en sujetos no alterados en tres especies de armadillos, chimpancés, monos mangabey, mono rhesus,, mono africano verde, ratas y ratones desnudos. No se ha demostrado que el chimpancé sea constantemente susceptible y por lo tanto requiere ser más estudiado para establecer su potencial utilidad. Los armadillos, debido a su facilidad de acceso, por lo menos en el Hemisferio Occidental, tienen grandes potenciales para experimentación, pero su utilidad en casi todas las áreas de experimentación casi no ha sido estudiada. Los ratones y las ratas desnudos tienen la ventaja de estar disponibles para laboratorios con el equipo adecuado; sin embargo, su cuidado es tedioso, su mantenimiento costoso y estos animales tienen vidas relativamente cortas. Las infecciones en los ratones desnudos parecen ser muy intensas y son, como las del armadillo, más graves que en la mayoría de los pacientes con lepra. Además, estos roedores, aunque no están alterados artificialmente, tienen una deficiencia inmunológica genética establecida en contraste con el sistema inmune de los individuos susceptibles a la lepra. El mono mangabey, aunque todavía en las etapas iniciales de experimentación, parece ofrecer la mejor esperanza hoy en día como modelo ideal para la lepra. Las únicas desventajas inmediatas son el ministro relativamente escaso de este animal y el costo de mantenimiento. Una enorme ventaja es la cercanía de esta especie a la especie humana. Las características de la enfermedad observada hasta el momento en los cinco sujetos estudiados sugieren que habrá muchas similitudes entre la lepra en el mono y el humano. El tiempo y los estudios los dirán

Acyclovir in the treatment of simian varicella virus infection of the African green monkey.

Acyclovir (9-(2-hydroxyethoxymethyl)guanine) administered as an intramuscular formulation twice daily at a dosage of 100 mg/kg per day prevented the development of disease in African green monkeys inoculated with simian varicella virus. Viremia, appearance of a vesicular rash, and elevations of serum transaminases, each indicative of infection, were suppressed by acyclovir treatment. Plasma concentrations of acyclovir were measured and showed rising levels after repeated intramuscular injection with a prolonged period of absorption of acyclovir into the plasma circulation. Investigation of antiviral efficacy after either intramuscular or intravenous acyclovir treatment showed both routes of administration to be effective in inhibiting simian varicella virus infection at the 100 mg/kg per day level. However, intravenous acyclovir 50 mg/kg twice daily did result in elevated values of blood urea nitrogen, creatinine, and serum transaminases.

Acyclovir treatment of experimental simian varicella infection of monkeys.

Replication of simian varicella virus (SVV) in Vero cell cultures was inhibited by acyclovir, 9-(2-hydroxyethoxymethyl)guanine (ACV), at a concentration of 10 micrograms/ml in culture medium. Intravenous administration of ACV at 10 mg/kg twice a day for 10 days or 15 mg/kg three times a day for 5 days to patas monkeys (Erythrocebus patas) beginning 48 h after SVV inoculation blocked the appearance of rash and other clinical symptoms but did not affect viremia. ACV treatment of African green monkeys (Cercopithecus aethiops) at 10 mg/kg twice a day by intravenous injection beginning 24 or 72 h after SVV inoculation and continuing for 10 days had no effect on clinical symptoms, including the development of rash, or on the appearance of viremia. The minimal therapeutic results could be due to the observation that doses of 10 or 15 mg/kg produced plasma levels of ACV which were lower than 5 micrograms/ml, the concentration that inhibited SVV multiplication in vitro, and decayed rapidly.

Ineffectiveness of adenine arabinoside and adenine arabinoside 5'-monophosphate in simian varicella infection.

Adenine arabinoside and adenine arabinoside 5'-monophosphate (ara-AMP) have been evaluated for antiviral activity against simian varicella virus infection in monkeys. In a preliminary study for toxicity, intramuscular injection of ara-AMP at 15 mg/kg per day as a single injection for 5 days to two normal patas monkeys caused no detectable local reaction, no weight loss or changes in serum transaminase levels, and no hematological abnormalities. When this dose was given in the treatment of four simian varicella virus-infected patas monkeys, no effect was observed on the clinical course of infection, as compared with four infected monkeys which received phosphate-buffered saline. Treatment was begun 43 h after virus inoculation and was continued for 16 days. Toxicity of intravenously administered ara-AMP at 100 to 50 mg/kg per day for 5 days to pairs of uninfected patas monkeys was evident by hematological and hepatic histological alterations, as well as the death of one monkey in each pair. No gross evidence of toxicity occurred in two monkeys which received 20 mg of ara-AMP per kg per day. The antiviral efficacy of intravenous treatment was studied in groups of four African green monkeys which received adenine arabinoside at 15 mg/kg per day or ara-AMP at 18.4 mg/kg per day. Drug administration began 48 h after inoculation with simian varicella virus and continued for 10 days. The monkeys that received treatment did not respond to infection differently from four infected control monkeys similarly treated with phosphate-buffered saline.

Phosphonoacetic acid in the treatment of simian varicella.

Phosphonoacetic acid inhibited replication of simian varicella virus (Delta herpesvirus) in tissue culture. The drug was tested in patas monkeys 40 h after infection with Delta herpesvirus. A total of 200 mg/kg per day was given intramuscularly, divided into two doses every day for a total of 10 days. The treated monkeys were protected from clinical illness, and Delta herpesvirus was not recovered from their lymphocytes. Complement-fixing and neutralizing antibody titers were significantly lower in phosphonoacetic acid-treated monkeys than in the untreated controls. In animals given the drug alone, there was dermatitis and blackening of the skin and hair, serum glutamic oxalacetic transaminase and serum glutamic pyruvic transaminase enzymes were significantly increased, and liver biopsy revealed diffuse cytoplasmic swelling and granulation of the hepatocytes. The therapeutic range of this drug should be studied carefully before considering its use in severe varicella-zoster infection in humans.

Effect of interferon respiratory infections of animals.

Several animal models are available for the evaluation of interferon in respiratory virus infections. Considerable variability exists among the respiratory viruses with respect to sensitivity to exogenous interferon or induced endogenous interferon. Due to this apparent variability, combinations of interferon with immune serum and chemotherapeutic agents may provide a means of more efficient control of respiratory infections.