Experimental leprosy in three species of monkeys.

Eleven mangabey monkeys inoculated with Mycobacterium leprae developed lepromatous-type leprosy. Nine of the mangabeys were inoculated with M. leprae isolated from a mangabey with naturally acquired lepromatous leprosy. Immune function was depressed in some of these animals after dissemination of the disease. Two mangabeys developed lepromatous leprosy after inoculation with human M. leprae passaged in an armadillo. Three rhesus and three African green monkeys inoculated with mangabey-derived M. leprae also developed lepromatous leprosy. Mangabeys may be the first reported nonhuman primate model for the study of leprosy. Rhesus and African green monkeys may also prove to be reproducibly susceptible to the disease.

A formalin-inactivated whole SIV vaccine confers protection in macaques.

A vaccine against human immunodeficiency virus (HIV) would be highly effective in stopping the acquired immunodeficiency syndrome (AIDS) epidemic. A comprehensive evaluation of potential vaccine methodologies can be made by means of the simian model for AIDS, which takes advantage of the similarities in viral composition and disease potential between simian immunodeficiency virus (SIV) infection of rhesus macaques and HIV infection in humans. Immunization with a formalin-inactivated whole SIV vaccine potentiated with either alum and the Syntex adjuvant threonyl muramyl dipeptide (MDP) or MDP alone resulted in the protection of eight of nine rhesus monkeys challenged with ten animal-infectious doses of pathogenic virus. These results demonstrate that a whole virus vaccine is highly effective in inducing immune responses that can protect against lentivirus infection and AIDS-like disease.

Arrest of epidermal growth factor-dependent growth in fetal hepatocytes after ethanol exposure.

Exposure of the fetal rat hepatocyte to ethanol in vitro blocks epidermal growth factor (EGF)-dependent cell replication. To define possible mechanisms for this growth arrest, we determined the effects of ethanol on EGF binding and EGF receptor (EGF-R) levels. During a 24-h exposure to ethanol (1.7 mg/ml, 31 mM), cell replication was completely blocked while EGF binding per cell doubled. This effect was no specific for EGF, with variable degrees of increased binding noted for insulin, transferrin, and glucagon. Significantly increased EGF binding was seen after 6 h of ethanol exposure, and both growth arrest and enhanced EGF binding were reversed within 12 h of ethanol withdrawal. Increases in both "high" and "low" affinity sites were seen, with no changes in the apparent Kd's. Total RNA, beta-actin mRNA, and EGF-R mRNA were increased 50-70% in ethanol exposed cells. However, direct measurements of EGF-R synthesis rates by [35S]methionine incorporation revealed no differences between control and ethanol exposed cells. Internalization of EGF-R was significantly altered by ethanol exposure. A 2-h incubation resulted in the internalization of 57% of the ligand in control cells, while only 31% of bound EGF was internalized in the ethanol exposed cells. Thus, the enhanced EGF binding may be due to decreased efficiency of internalization.

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.

Bovine serum albumin as a catalyst. VI. Specificity of several nucleophilic groups in the protein for N-dansylaziridine.

The reaction of N-dansylaziridine with serum albumin (both bovine and human) results in incorporation of about 3 mol of covalently bound dansyl label per mol protein. This indicates that a number of nucleophilic groups in these proteins (in addition to the free sulfhydryl group) will react with this reagent. The reaction has been studied in detail for bovine serum albumin and the results suggest that one of the sites labelled by the reagent may be at the unusual "catalytic site" responsible for the enzyme-like activity of bovine serum albumin recently described (Taylor, R.P., Chau, V., Bryner, C. and Berga, S. (1975) J. Am. Chem. Soc. 97, 1934-1942). The reaction of N-dansylaziridine with a variety of other proteins indicates a pattern of labelling consistent with high specificity for the sulfhydryl group. The explanation for the unexpected excess reactivity of albumin with the "sulfhydryl specific" reagent N-dansylaziridine must be related to the three-dimensional structure in albumin which enables a number of specific residues to manifest unusually high degrees of nucleophilic reactivity.

Efficacy of SIV/deltaB670 glycoprotein-enriched and glycoprotein-depleted subunit vaccines in protecting against infection and disease in rhesus monkeys.

Immunization with an inactivated whole-virus vaccine is highly effective in preventing lentivirus infection. The viral protein(s) essential to the induction of protective responses, however, have not been identified. To define the role of virion components in the induction of protective immunity, we evaluated the efficacy of glycoprotein-enriched and glycoprotein-depleted simian immunodeficiency virus (SIV) subunit vaccines prepared by lentil-lectin affinity chromatography of gradient-purified virions using the immunization and challenge regimen previously found successful with an inactivated whole-virus vaccine. Infection was determined by successful recovery of virus, the induction of SIV-specific antibody responses, and infection of naive recipients by inoculation with lymph-node-derived lymphocytes from the vaccinates. Immunization with the glycoprotein-enriched preparation prevented infection in two out of four monkeys, whereas the glycoprotein-depleted vaccine failed to prevent infection in all four vaccinates tested. However, the glycoprotein-depleted vaccine appeared to moderate the progression of SIV-induced disease compared with non-immunized infected control monkeys inoculated with the same challenge dose. These data suggest that subunit vaccines containing sufficient quantities of viral glycoproteins can protect against SIV infection, whereas subunit vaccines composed predominantly of viral core proteins cannot. The development of effective vaccines against HIV infection should include studies on the optimum presentation of the viral envelope glycoproteins to produce long-term broadly protective immune responses.

Lung gene therapy: in vivo adenovirus-mediated gene transfer to rhesus monkey airway epithelium.

Somatic gene therapy of lung disorders such as cystic fibrosis (CF) aims at introducing the therapeutic gene into respiratory epithelium. We have tested the ability of recombinant human adenovirus to infect rhesus monkey airway epithelium in vivo. Application of adenovirus harboring the lacZ marker gene to the airway surface resulted in large patches of lacZ-positive cells in the trachea, bronchi, and bronchioles, 6 days after virus exposure, indicating a successful transfer of the lacZ gene to respiratory epithelium. Microscopic analysis showed that basal, mucous goblet, and ciliated cells were lacZ positive. In addition, gene transfer to the submucosal glands was observed. Pathological examination of the organs revealed no virus-mediated toxic effects to the lungs and other organs. Using polymerase chain reaction (PCR) analysis we found no spread of the virus to blood or any organ tested. These results indicate the potential use and safety of adenoviruses as a tool in human gene therapy procedures aimed at pulmonary diseases.

Immunomodulation and adenoviral gene transfer to the lungs of nonhuman primates.

Previous data from our laboratory and others have demonstrated a critical role for the CD4+ T lymphocyte in in vivo immune responses to recombinant adenoviral vectors. In rodent models, this subset of T cells is required for T cell proliferation, subsequent cytotoxic T cell generation, and production of anti-adenoviral antibodies by B cells. Both depleting and nondepleting anti-CD4 antibodies can attenuate these immune responses to recombinant adenovirus. On the basis of these data, we hypothesized that a nondepleting CDR-engrafted anti-human CD4 antibody (OKT4A) with cross-reactivity to rhesus macaques would attenuate both T and B cell responses to intrapulmonary administration of recombinant adenovirus and permit prolonged reporter gene expression and permit secondary gene transfer. Juvenile rhesus macaques were treated with PBS or OKT4A antibody (10 mg/kg) daily beginning 1 day prior to and up to 11 days after gene transfer. OKT4A resulted in significant attenuation of lymphocyte recruitment into the lung, lymphocyte-proliferative responses to both adenovirus capsid proteins and transgene protein, and adenovirus-induced interferon-gamma elaboration in whole blood and hilar lymph nodes. However, OKT4A was ineffective in attenuating adenovirus-induced IL-4 production in whole blood or hilar lymph nodes, generating neutralizing anti-adenoviral antibodies, or permitting secondary gene transfer. As all the monkeys in this protocol had baseline-detectable anti-adenoviral antibodies by ELISA that were nonneutralizing, analogous to most patients with cystic fibrosis, we postulate that anti-CD4 did not block the proliferation of memory B cells. Moreover, these data suggest that for transient immunomodulation to be successful, strategies need to focus specifically on B cell activation independent of CD4+ T cell help.

Liver-directed gene transfer in non-human primates.

To develop a primate model for liver-directed gene therapy, we studied several gene transfer vehicles and routes in eight rhesus monkeys (Macaca mulatta). For this purpose, we used first-generation, replication-deficient adenoviral vectors carrying the Escherichia coli lacZ gene (Ad.CMVlacZ) or a lacZ-containing plasmid (pCMV beta) with lipofectamine for transfection. The reporter gene construct was infused into either the portal vasculature, common bile duct, or saphenous vein. Adenovirus-mediated gene transfer via the portal vein resulted in expression of lacZ in over 70% of hepatocytes by days 3-7, but was accompanied by acute hepatitis. Adenovirus-mediated gene transfer via the common bile duct resulted in lacZ expression in less than 10% of hepatocytes and was accompanied by portal inflammation. The animals mounted a significant immune response, as demonstrated by adenoviral antigen-induced T-cell proliferation and production of neutralizing anti-adenovirus antibodies and antibodies to E. coli beta-galactosidase (beta-Gal). Activation of the immune response was associated with rapid decrease of the reporter gene by days 13-21. Lipofectamine-mediated gene transfer was inefficient, and no lacZ expression in the liver was detected. To limit the host immune response, 4 animals were immunosuppressed by cyclophosphamide/prednisone and then infused with the Ad.CMVlacZ via the portal vein or the saphenous vein. The monkeys showed sustained expression of lacZ for up to 35 days with no evidence of inflammation. The primates transduced via the saphenous vein showed a level of beta-Gal expression in the liver similar to that of the portal vein-infused animals. In conclusion, adenovirus-mediated gene transfer to non-human primate livers via the portal vein or saphenous vein is efficient, but it results in transient expression and is accompanied by an immune response to both vector and transgene products and acute hepatitis, whereas lipofectamine-mediated transfer is inefficient. Manipulation of the host immune response may expand potential applications of adenoviral vectors for liver-directed gene transfer.

Simian AIDS-associated lymphoma in rhesus and cynomolgus monkeys recapitulates the primary pathobiological features of AIDS-associated non-Hodgkin's lymphoma.

Non-Hodgkin's lymphomas occur with increased frequency (3-6%) in HIV-infected individuals. These AIDS-associated lymphomas (AALs) exhibit characteristics that distinguish them from lymphomas in the general population. A proposed model for the pathogenesis of AAL includes the following: (1) Tumorigenesis is multistep; (2) tumors occur in long-term survivors; (3) tumors are of clonal B cell origin; (4) HIV acts early and is an indirect effector; (5) tumor cells are infected with EBV; and (6) specific genetic lesions occur in tumor cells. Many aspects of this process remain to be tested in an animal model system. Since 1984, necropsy examinations have been performed on more than 1000 SIV-infected rhesus and cynomolgus monkeys at the Tulane Regional Primate Research Center. Lymphoid malignancies were detected in a proportion of SIV-infected animals. These SAIDS-associated lymphomas (SALs) have been studied to determine the extent to which their pathological features recapitulate a working model for the pathogenesis of AAL. The results show that lymphomas occur in SIV-infected rhesus macaques at 4% incidence, similar to that of AAL, and that the incidence of SAL in cynomolgus macaques is eightfold higher. Analysis of SAL from both species of macaques demonstrated significant similarity to the hallmark pathobiological features of AAL. These findings indicate that the HIV-infected human and the SIV-infected macaque share a common pathobiology and mechanism of lymphomagenesis.

Distribution of SIV in lymph nodes of serially sacrificed rhesus monkeys.

Rhesus monkeys were inoculated with SIVDeltaB670 and sacrificed 2, 4, 8, and 24 weeks after inoculation or when moribund. Two monkeys predicted to have a rapid disease course and two predicted to have a slower disease course were sacrificed at each time point. Lymph nodes were studied by histopathology, immunohistochemistry, in situ hybridization, electron microscopy, flow cytometry for lymphocyte subsets, and mitogen responsiveness. A greater selective decrease in peripheral CD4+CD29+ (helper-inducer/memory) T cells occurred in monkeys with high antigenemia. Although the percentage of CD8+ lymphocytes was increased and the CD4+/CD8+ ratio decreased in all infected groups, there were no consistent differences between monkeys with high or low antigenemia in lymph node lymphocyte subsets. Blastogenic responses of lymph node lymphocytes to PHA, ConA, or PWM were not significantly altered in infected monkeys. A reticular pattern typical of antigen deposition within germinal center follicular dendritic cells was seen in three monkeys with atrophic lymph nodes, high serum antigenemia, and a low percentage of circulating CD4+/CD29+ cells. More individually stained cells were in monkeys with high serum antigen and in moribund animals. By in situ hybridization, most monkeys had signal in a reticular pattern of germinal centers. Animals with higher levels of serum antigenemia tended to have more infected cells and a more intense signal. Extracellular virions were found between the FDC foot processes in the germinal centers of lymph nodes. Disease course was already established 2 weeks after inoculation.

Variation in simian immunodeficiency virus env V1 region in simian AIDS-associated lymphoma.

Genetic variation of SIV env during the course of infection provides a large population pool that is continually shaped by selective forces in vivo and may influence the development of clinical disease. SAIDS-associated lymphoma (SAL) in the SIV-infected macaque is typically a clonal or oligoclonal mass of B cell origin, extranodal in anatomic distribution, in which SIV is restricted largely to infiltrating macrophages. To explore the degree of genetic variation in SIV env represented in SAL, a 480-bp DNA fragment containing the V1 region was PCR amplified from seven cases of SAL and from a nonneoplastic lymph node of an SIV-infected macaque. The nucleotide sequence of the V1 region was determined from at least 10 clones from multiple independent amplification reactions of each tissue. Overall, the degree of V1 variability within lymphomas was found not to be restricted but to resemble the heterogeneity reported in SIV-infected lymphoid and other tissues. V1 variation in the nonneoplastic lymph node was unexpectedly limited, perhaps related to the unusual disease condition associated with SAIDS in that animal. Unlike observations from SIV-infected tissues of animals without neoplastic disease, no increase was detected in the number of O- or N-linked glycosylation sites in the V1 regions isolated from lymphomas as compared with the original inoculum. These findings suggest that, within the microenvironment of the lymphoma, the immune evasion conferred by increased glycosylation may offer little selective advantage.

Rhesus lymphocryptovirus infection during the progression of SAIDS and SAIDS-associated lymphoma in the rhesus macaque.

SAIDS-associated lymphoma (SAL) represents a monoclonal expansion of B-cell origin in which simian immunodeficiency virus (SIV) infection is not detected. However, tumor cells are frequently infected with rhesus lymphocryptovirus (RhLCV), a rhesus homologue of Epstein-Barr virus (EBV). In previous studies, the incidence of RhLCV infection in SAL was determined to be 89% as measured by polymerase chain reaction (PCR) and/or in situ hybridization. The main objective of the present study was to ascertain whether the level of RhLCV infection in the SIV-infected macaque is influenced as a function of SAIDS progression, and/or whether increased levels of RhLCV infection may correlate with the development of SAL. To this end, RhLCV infection was evaluated in three independent groups: (1) in lymphomas from SIV-infected rhesus macaques, (2) in peripheral blood mononuclear cells (PBMC) from a cohort of 69 randomly selected healthy animals, and (3) in PBMC collected from 22 SIV-infected animals at various times during progression to SAIDS or SAL. The relative levels of RhLCV infection were evaluated by PCR/Southern blot analysis, visual comparison to a standard dilution series, and assignment of relative signal intensity to a uniform classification scheme. The data show that SIV-infected monkeys have a generally higher RhLCV load in PBMC than do healthy animals, but that the virus load varies widely among animals during disease progression. Increased RhLCV load does not occur uniformly during the progression of SAIDS, although evidence indicates an increased RhLCV viral load in the development of SAL.

Neonatal disease induced by SIV infection of the rhesus monkey (Macaca mulatta).

Seven 72-hr-old Indian origin rhesus monkeys (Macaca mulatta) were inoculated with 10 animal ID50 of SIV/DeltaB670. Nine age-matched animals were used as uninoculated controls. All seven inoculated animals became infected as verified by viral isolation and SIV p26 antigenemia. Five of seven infected animals died within a mean of 31 days (range, 26-41 days), with high levels of antigenemia beginning 1-2 weeks postinoculation (PI) that persisted until death. Absolute lymphocyte numbers were within normal limits in all animals in both groups throughout the study. Inoculated animals that died within a mean of 31 days (short-term survivors) had significantly lower numbers of CD4+CD29+ (helper/inducer) lymphocytes than did long-term surviving inoculated animals through 3 weeks PI. Numbers of CD4+ lymphocytes were no different when controls were compared to all inoculated animals through 4-5 weeks PI. The two inoculated animals surviving 216 and 423 days PI (long-term survivors) did demonstrate declining CD4+ cells, but only late in disease. CD8+ lymphocytes were significantly lower in short-term survivors when compared to long-term survivors through 5 weeks PI. Antibody production against SIV viral proteins was detected only in the long-term survivors and was similar to results from past studies in juveniles. Clinical signs in the inoculated group were consistent with those seen in past studies on older animals. Persistent bacterial infections, primarily of the GI and respiratory tracts, were seen in the infected group. Aside from the lack of some opportunistic infections such as cytomegalovirus (CMV) and Pneumocystis carinii, necropsy findings were not different when compared to past studies on juvenile animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Ontogenetic and phylogenetic evaluation of the presence of fibrin-type fibrinoid in the villous haemochorial placenta.

The hypothesis that fibrin type fibrinoid deposition on villi is unique to the term human placenta was tested. Bright-field microscopy was used to examine sections of first and second trimester human placental villi and tissues from three animal species that have villous haemochorial placentae similar to the human: the armadillo, the baboon and the rhesus. Sections stained with haematoxylin and eosin showed fibrin type fibrinoid deposits were hypocellular, eosinophilic masses attached to the surface of villi examined from both the human and the animal species. The deposits were located at discontinuities in the syncytiotrophoblast layer, and the fibrinoid provided a matrix for trophoblast re-epithelization of the villous surface. It is concluded that fibrin-type fibrinoid is not unique to the term human placenta. The presence of the syncytiotrophoblast discontinuities associated with the fibrinoid deposition must be considered in models of maternal-fetal exchange in the villous haemochorial placenta.

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.

Naturally acquired and experimental leprosy in nonhuman primates.

Naturally-acquired leprosy has been observed in chimpanzees and sooty mangabey monkeys. Experimental multibacillary leprosy was established in 24 of 36 mangabey monkeys, 7 of 34 rhesus monkeys, and 15 of 19 African green monkeys following intravenous and intradermal inoculation of Mycobacterium leprae. The experimental disease strongly resembles leprosy in humans clinically, histopathologically, and immunologically. Thus, in addition to nine-banded armadillos in Louisiana and Texas, chimpanzees and sooty mangabeys in Africa, in the wild or in captivity, may serve as a zoonotic source of M. leprae. Investigators using chimpanzees and monkeys should be alerted to the possibility of naturally-acquired leprosy.

Plasmodium coatneyi in the rhesus monkey (Macaca mulatta) as a model of malaria in pregnancy.

Pregnant women with Plasmodium falciparum infection are at increased risk for complications such as anemia and cerebral malaria. In addition, the infants of these women suffer intrauterine growth retardation (IUGR), low birth weight (LBW), congenital infection, and high infant mortality. Although much has been learned from studies of malaria during human pregnancy, progress has been limited by the lack of a suitable animal model. Nonhuman primates are of particular interest because, other than the armadillo, they are the only animals with a discoidal, villous, hemochorial placenta like that of humans. We have established a model of malaria during human pregnancy by inoculating pregnant rhesus monkeys (Macaca mulatta) with Plasmodium coatneyi (a sequestering parasite) during the first trimester. In our initial experiment, four monkeys were inoculated with a fresh inoculum containing 10(8) viable parasites from an infected donor monkey. All four monkeys became parasitemic seven days postinoculation (PI) and three monkeys aborted 7-10 days PI coincident with high peak parasitemias (41,088-374,325 parasites/mm3). Although abortion is one of the outcomes observed in Plasmodium-infected women, the intent of this study was to examine the effects of Plasmodium infection throughout gestation. Since the rapid onset of high parasitemia may have been responsible for the abortions, a decision was made to reduce the size of the effective inoculum. Six additional pregnant monkeys were inoculated with a frozen isolate taken from the same donor containing 10(6) parasites. These six animals became parasitemic by 14 days PI and, along with monkey E412, carried their infants to term. These seven infants weighed significantly less at term than the infants of uninfected mothers (P = 0.0355). Symmetrical IUGR was detected by ultrasound in one fetus with an LBW of 334 g. Another LBW infant (300 g) had asymmetrical growth retardation, which has been associated with uteroplacental insufficiency and was consistent with the lower placental weights found in infected dams compared with controls (P = 0.0455). The infant with symmetric IUGR died at five days of age, while the other is alive but congenitally infected. The IUGR, LBW, congenital infection, postnatal infant mortality, and early abortions observed in these animals suggest that P. coatneyi in pregnant rhesus monkeys is a valid model of malaria in human pregnancy. This model should provide the opportunity to study questions about malaria in pregnancy that have been difficult to study in humans.

Placental changes associated with fetal outcome in the Plasmodium coatneyi/rhesus monkey model of malaria in pregnancy.

Term placentas collected surgically from seven Plasmodium coatneyi-infected rhesus monkeys, one abortion, and five controls were evaluated histopathologically. The placentas from Plasmodium-infected dams had more significant pathologic changes than those from controls for six parameters (P < 0.05) and higher numbers of activated (LN5 + Zymed) macrophages in the intervillous space (IVS) (P = 0.0173). Total parasite load (TPL) was defined as the sum of all weekly peripheral infected red blood cell counts for each trimester and for the entire pregnancy. High first trimester PLs were more likely to result in fetal demise (P = 0.0476) or increased placental damage in surviving infants. As trimester 2-3 TPL increased, so did the number of activated macrophages (P < 0.05) and the total malaria pigment scores (P < 0.05). Low birth weight (LBW) and intrauterine growth retardation (IUGR) were associated with high pigment scores and high numbers of activated macrophages in the IVS. High placental damage scores were not associated with IUGR, LBW, or early infant mortality.

Experimental leprosy in African green monkeys (Cercopithecus aethiops): a model for polyneuritic leprosy.

Three African green monkeys (Cercopithecus aethiops) were inoculated intravenously and intracutaneously with Mycobacterium leprae derived from a naturally infected mangabey monkey. All developed cutaneous lesions at inoculation sites. One developed disseminated cutaneous lesions, while the cutaneous lesions in the other two regressed and eventually disappeared. The animals were examined at necropsy five years after inoculation. All three had active leprosy infection in peripheral nerves with extensive inflammation and fibrosis. The disease histologically resembled borderline-lepromatous leprosy. These findings add a new dimension to animal models of leprosy.