Rhesus rhadinovirus infection in healthy and SIV-infected macaques at Tulane National Primate Research Center.

Rhesus rhadinovirus (RRV) infection was quantified in peripheral blood mononuclear cells (PBMC) from healthy and simian immunodeficiency virus (SIV)-infected rhesus macaques (Macaca mulatta) at the Tulane National Primate Research Center and in a large collection of simian acquired immunodeficiency syndrome--(SAIDS)-associated lymphomas. Quantification of RRV load was performed by real-time PCR using amplification primers specific for the RRV interleukin-6 homologue (RRV vIL-6). RRV infection was detected infrequently and at low levels in PBMC of randomly selected healthy animals. Examination of longitudinally collected PBMC from 22 SIV-infected animals throughout progression to SAIDS revealed similarly low RRV loads that sometimes increased with advancing disease. RRV infection was detected more frequently in the peripheral blood of SIV-infected animals than in healthy animals. Examination of SAIDS-associated lymphomas showed that RRV is rare within the tumor mass, likely representing infection in an occasional tumor-infiltrating cell or contaminating blood. The results indicate that RRV infection in PBMC is not predictive of, and is apparently not required for, development of lymphoma or hyperplastic lymphadenopathy in SIV-infected animals at TNPRC.

Anti-leprosy protective vaccination of rhesus monkeys with BCG or BCG plus heat-killed Mycobacterium leprae: lepromin skin test results.

Groups of rhesus monkeys (RM) were vaccinated and boosted with living Mycobacterium bovis Bacillus Calmette-Guerin (BCG) or BCG + low dose (LD) heat-killed Mycobacterium leprae (HKML) or high dose (HD) HKML or were unvaccinated. Animals vaccinated with BCG + LD and HD HKML were lepromin skin tested 2 weeks after boosting. All groups were lepromin tested 37 and 46 months after challenge with live M. leprae. Fernandez (72 h) and Mitsuda (28 day) responses were recorded. Ten of 10 rhesus monkeys in each of the two BCG + HKML-vaccinated groups significantly converted to strong positive Fernandez status within 2 weeks of boosting, compared to one of six positives in the unvaccinated unchallenged normal control group. Both BCG + HKML groups were significantly protected from clinical leprosy. Six of 10 in each of the two BCG + HKML groups significantly converted to Mitsuda positivity within 2 weeks of boosting compared to zero of six in the normal control group. The sizes of the Mitsuda responses were larger in the LD group than the HD HKML vaccinated/boosted group, suggesting suppression by vaccination with higher doses of HKML in combination with BCG. Fernandez responses were negative in normal RM as well as in the unvaccinated, ML-challenged group and the BCG-vaccinated, ML-challenged group at 37 or 46 months after ML inoculation, although the BCG-vaccinated group was significantly protected from leprosy and the unvaccinated group was not. In contrast, at 37 months the Fernandez reaction was positive in the BCG plus LD and the BCG plus HD HKML-vaccinated groups, both of which were significantly protected from clinical leprosy. By 46 months, the Fernandez responses were below significance in all groups. Thus, Fernandez reactivity is not a reliable correlate to protection from experimental leprosy in RM. Mitsuda responses became strongly positive in all four ML-challenged groups by 37 months and remained strongly positive at 46 months after ML inoculation, suggesting that strong Mitsuda reactivity reflects responses to living ML. BCG or BCG + LD or HD HKML vaccination/boosting of RM produced significant clinical protection from leprosy and there was a good correlation between protection from LL forms of leprosy and positive Mitsuda skin test responses after challenge with live ML. Positive Mitsuda responses were generated in essentially all individuals after challenge with live ML, and this response was primed by prior vaccination/boosting with BCG + HKML as shown by conversion to positivity 2 weeks after boosting. The data show that resistance to clinical leprosy is reflected by Mitsuda responses in ML-exposed RM, similar to results from human studies, and confirm the suitability of RM as a model for leprosy vaccine studies.

Endometrial hyperplasia, polyps, and adenomyosis associated with unopposed estrogen in rhesus monkeys (Macaca mulatta).

The purpose of this study was to evaluate the effects of estrogen and progesterone on the vaginal mucosa and their role in vaginal transmission of simian immunodeficiency virus. Incidentally, endometrial hyperplasia was observed in estrogen-treated monkeys at necropsy. Six adult female rhesus monkeys (Macaca mulatta) were ovariectomized and 120 days later received two subcutaneous implants, each containing 200 mg estradiol. The animals were sacrificed 17-27 months later and the uterus examined at necropsy. All the monkeys had simple endometrial hyperplasia, some with polyps or adenomyosis, at the time of necropsy. The severity of the changes correlated with the time between implantation and necropsy. The lesions were similar to endometrial hyperplasia caused by unopposed estrogen in women, but occurred over a time period that is suitable for experimental manipulation. Rhesus monkeys could be used as a model to test the safety of various combinations of sex steroids for the prevention of postmenopausal symptoms in women.

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.

Interactions between Mycobacterium leprae and simian immunodeficiency virus (SIV) in rhesus monkeys.

Groups of rhesus monkeys were inoculated with: 1) simian immunodeficiency virus (SIV)B670 alone; 2) Mycobacterium leprae alone; 3) SIV plus M. leprae on the same day; and 4) M. leprae 2 weeks after SIV. Animals were monitored at intervals for virus loads, antibody responses to M. leprae glycolipid antigens and to SIV Gp120, T-cell CD4+ and CD4+ CD29+ subset percentages, leprosy and acquired immunodeficiency syndrome (AIDS) clinical symptoms. Five out of six animals developed leprosy in each co-inoculated group, compared to one out of six in the M. leprae-only-inoculated group, indicating that M. leprae/SIV co-infection increases the susceptibility to leprosy, regardless of the timing of the two infections. Animals in the co-infected group that received M. leprae 2 weeks after SIV had a significantly slower rate of AIDS progression and long-term survival was significantly greater (three out of six) compared to the group inoculated with SIV alone (zero out of seven). All M. leprae-only-inoculated animals (six out of six) survived. Post-SIV-inoculation, a rapid decrease in the percentages of CD4 + and CD4 + CD29 + T-cells was observed in the SIV-only-inoculated group that was significantly blocked by co-inoculation with M. leprae 2 weeks after SIV, but not by SIV on the same day. The virus load set point was increased by approximately two logs in the group inoculated with M. leprae and SIV on the same day compared to SIV 2 weeks prior to M. leprae or the SIV-only-inoculated group. The results indicate that M. leprae, inoculated 2 weeks after SIV, decreased the pathogenicity of SIV compared to inoculation of M. leprae and SIV on the same day or SIV alone. The decreased pathogenicity correlated with a diminished loss of CD4 + and CD4 + CD29 + T-cell subsets in the group inoculated with M. leprae 2 weeks after SIV compared to the group inoculated with SIV alone. IgG antibody responses to M. leprae-specific cell wall phenolic glycolipid-I antigen were inhibited by 2-week-prior or same-day SIV co-inoculation compared to M. leprae-only inoculated animals. The IgG anti-lipoarabinomannan antibody response was enhanced in the group inoculated with M. leprae and SIV on the same day compared to the groups inoculated with M. leprae alone or SIV 2 weeks prior to M. leprae. Antibody responses to SIV Gp120 antigen were unimpaired in both co-inoculated groups compared to SIV-only-inoculated groups. The antibody results show that the immune responses to SIV and M. leprae are interrelated in SIV/M. leprae co-infected animals.

Estrogen protects against vaginal transmission of simian immunodeficiency virus.

Postmenopausal women and women who use injectable, progestin-based contraceptives are at increased risk of human immunodeficiency virus (HIV) infection, suggesting that progesterone and estrogen affect HIV-1 vaginal transmission. To evaluate the individual roles of these sex hormones in vaginal transmission, ovariectomized female macaques were treated with either progesterone or estrogen followed by intravaginal inoculation with SIVmac. All 6 untreated control macaques and 5 (83%) of 6 progesterone-treated animals became infected following intravaginal SIV inoculation. Conversely, none of 6 estrogen-treated macaques was infected. Vaginal subepithelial inoculation of estrogen-treated animals resulted in infection, which shows that the block occurred at the vaginal epithelium and/or lumen. These data suggest that estrogen-deficient women are at increased risk of HIV infection, because their vaginal microenvironments are rendered more susceptible. Moreover, topical vaginal estrogen therapy may be an effective means of reducing HIV vaginal transmission in these high-risk groups.

Antileprosy protective vaccination of rhesus monkeys with BCG or BCG plus heat-killed Mycobacterium leprae: immunologic observations.

Groups of rhesus monkeys were vaccinated and boosted with Mycobacterium bovis bacillus Calmette Guerin (BCG) or BCG plus low-dose (LD) or high-dose (HD) heat-killed M. leprae (HKML), or were unvaccinated. Prior to and following vaccination-boosting and subsequent M. leprae (ML) challenge, these and unvaccinated, unchallenged control monkeys were observed longitudinally for approximately 3 years. Vaccination with BCG plus HKML initially stimulated significant in vitro blood mononuclear cell blastogenic responses to lepromin, which returned to baseline post-boosting and post-live-ML-challenge, minimally reappearing significantly 2 years post-ML-challenge. Vaccination with BCG failed to stimulated positive blastogenic responses to lepromin before ML-challenge but small, marginally positive, intermittent responses were seen post-ML-challenge. Compared to the unvaccinated ML-challenged group, significant increases in the numbers of blood CD4+ and CD8+ T-cell subsets and an increased CD4+:CD8+ ratio were observed in both BCG plus HKML-vaccinated, ML-challenged groups, but not in the BCG-only-vaccinated, ML-challenged group. CD4+CD29+ and CD4+CD45RA+ subset numbers increased significantly over time in only the BCG plus LD HKML-vaccinated, ML-challenged group. Compared to unvaccinated, ML-challenged groups, vaccination with BCG or BCG plus HKML followed by ML-challenge produced lower IgM:IgG antiphenolic glycolipid-I (PGL-I) serum antibody ratios and protected rhesus monkeys from clinical leprosy, consistent with prior observations that low IgM:IgG anti-PGL-I responses correlated with resistance to and protection from leprosy.

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.

Antileprosy protective vaccination of sooty mangabey monkeys with BCG or BCG plus heat-killed Mycobacterium leprae: immunologic observations.

Groups of sooty mangabey monkeys (SMM) were vaccinated and boosted with Mycobacterium bovis bacillus Calmette-Guerin (BCG), or BCG + low-dose (LD) or high-dose (HD) heat-killed M. leprae (HKML), or were unvaccinated. Prior to and following vaccination-boosting and subsequent M. leprae (ML) challenge, these and unvaccinated, unchallenged control monkeys were immunologically observed longitudinally for approximately 3 years. SMM [multibacillary (MB) leprosy-prone as a species] were not protected clinically by BCG or BCG + HKML, although the disease progress was slowed by vaccination with BCG alone. The longitudinal immune response profiles to BCG or BCG + HKML in SMM showed that: 1) vaccination with BCG or BCG + HKML initially stimulated significant in vitro blood mononuclear cell blastogenic responses to ML antigens, which returned to baseline post-boosting and post-live ML challenge; 2) BCG + LD HKML-vaccinated groups gave the largest blastongenic response (SI = 23) followed by the BCG + HD HKML group (SI = 14.5) and by the BCG-only vaccinated group (SI = 3.6); 3) significantly diminished numbers of blood CD4+ (helper) and CD4+CD29+ (helper-inducer) T-cell subsets were observed longitudinally in all ML-challenged groups compared to controls regardless of whether they had been vaccinated or not; 4) CD8+ (suppressor) T-cell numbers remained longitudinally constant, on average, in all ML-challenged groups (vaccinated or not) compared to controls; 5) there was a significant decrease in the CD4+:CD8+ ratio over time in all ML-challenged groups (vaccinated or not); 6) vaccination with BCG or BCG + LD or HD HKML resulted in significantly increased numbers of CD4+CD45RA+ (suppressor-inducer) T cells longitudinally compared to the unvaccinated, ML-challenged control group; and 7) over time, vaccination with BCG + HKML followed by live ML-challenge produced higher IGM:IgG antiphenolic glycolipid-I (PGL-I) serum antibody response ratios than BCG-only vaccinated, ML-challenged monkeys or unvaccinated, ML-challenged SMM, consistent with prior observations that IgG anti-PGL-I responses correlate with resistance to and protection from clinical leprosy and IgM anti-PGL-I responses correlate with increased susceptibility.

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.

Association of simian virus 40 with a central nervous system lesion distinct from progressive multifocal leukoencephalopathy in macaques with AIDS.

The primate polyomavirus SV40 is known to cause interstitial nephritis in primary infections and progressive multifocal leukoencephalopathy (PML) upon reactivation of a latent infection in SIV-infected macaques. We now describe a second central nervous system manifestation of SV40: a meningoencephalitis affecting cerebral gray matter, without demyelination, distinct from PML. Meningoencephalitis appears also to be a primary manifestation of SV40 infection and can be seen in conjunction with SV40-induced interstitial nephritis and pneumonitis. The difference in the lesions of meningoencephalitis and PML does not appear to be due to cellular tropism, as both oligodendrocytes and astrocytes are infected in PML and meningoencephalitis, as determined by in situ hybridization or immunohistochemistry for SV40 coupled with immunohistochemistry for cellular determinants. This is further supported by examination of SV40 nucleic acid sequences from the ori-enhancer and large-T-antigen regions, which reveals no tissue-or lesion-specific variation in SV40 sequences.

Experimental leprosy in rhesus monkeys: transmission, susceptibility, clinical and immunological findings.

A total of 46 Rhesus monkeys (RM) was inoculated with Mycobacterium leprae (ML) and followed clinically and immunologically for extended periods. Twenty-one (45.7%) of the RM developed leprosy spanning the known leprosy spectrum, with six of 21 (28.6%) having disease in the borderline lepromatous to lepromatous area of the spectrum. RM with paucibacillary forms of leprosy produced predominantly IgG anti-phenolic glycolipid (PGL-I) antibodies and positive lepromin skin test and/or in vitro blastogenesis responses; IgM anti-PGL-I predominated in animals with BB-LL leprosy and correlated with negative immune responses to lepromin. IgG anti-PGL-I antibodies persisted in a number of RM for several years without histopathological evidence of leprosy, suggesting possible persisting subclinical infection. The data show that RM are a valuable model for the study of leprosy. Eleven of the 46 RM were inoculated with ML from sources infected with simian immunodeficiency virus (SIV), the monkey counterpart to the human immunodeficiency virus (HIV). The possible effect of SIV on the clinical outcome of ML infection could not be determined due to insufficient numbers of animals to yield statistically significant results.

Identification of SV40 in brain, kidney and urine of healthy and SIV-infected rhesus monkeys.

Recent reports of simian virus 40 (SV40) sequences in human tumors have prompted investigations into the poorly understood association of this polyomavirus with its primate host, the rhesus monkey (Macaca mulatta). In the present study we have used PCR to analyze tissues from 20 monkeys for the presence of SV40. Five of the animals, which were infected with simian immunodeficiency virus (SIV), were found to exhibit SV40-induced lesions and to have SV40 sequences present in their kidney and brain. Lesions associated with SV40 were not observed in 15 SIV monkeys, and SV40 DNA was detected in kidney and urine of only one of these animals. Three regions of SV40 DNA were examined in each tissue: the non-coding transcriptional control region (TCR), the sequences encoding the host range domain (HRD) within the carboxy-terminus of T antigen (TAg), and a portion of the VP1 gene. Each region contained nucleotide alterations compared to the SV40 reference strain 776. In all six animals, the TCR had an archetype structure containing a single 72 bp enhancer element. In addition, the TCR amplified from two animals lacked one of three copies of a GC-rich 21 bp repeat which is part of the promoter in strain 776. Multiple clones of unique HRD sequences were derived from different animals, and in some instances from the same animal. No correlation was found between a particular HRD sequence and its presence in a specific tissue type. Nucleotide changes identified within the VP1 gene indicate that this region, as with the closely-related human polyomavirus JCV, may permit the typing of the virus into individual strains. This study is the first to characterize SV40 sequences present in both healthy and SIV-infected animals and supports the suggestion that strain 776 is not the predominant type of SV40 circulating in its natural host.

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.

Protective immunization of monkeys with BCG or BCG plus heat-killed Mycobacterium leprae: clinical results.

Rhesus and sooty mangabey monkeys (RM and SMM) were vaccinated and boosted with BCG or BCG + low dose (LD) or high dose (HD) heat-killed Mycobacterium leprae (HKML). One group was not vaccinated. Except for a group of controls, all monkeys were challenged with live M. leprae. All animals were studied longitudinally to determine antileprosy protective efficacy. BCG reduced the numbers of RM with histopathologically-diagnosed leprosy by 70% and slowed and ameliorated the appearance of symptoms. BCG + LDHKML reduced the number of RM with leprosy by 89% and BCG + HDHKML by 78%. BCG did not protect SMM from developing leprosy, but disease progress was slowed; disease in SMM was exacerbated by the addition of HKML to the vaccine. RM, as a species, are prone to paucibacillary (PB) forms of leprosy, whereas SMM are prone to multibacillary (MB) forms. Thus, BCG vaccination offers significant protection from clinical disease and slows/ameliorates the rate of progression/degree of disease at the PB end and appears to at least ameliorate symptoms at the MB end of the leprosy spectrum. BCG + HKML protects at the PB end and exacerbates disease progress at the MB end of the leprosy spectrum.

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.

Genetic galactocerebrosidase deficiency (globoid cell leukodystrophy, Krabbe disease) in rhesus monkeys (Macaca mulatta).

Globoid cell leukodystrophy, or Krabbe disease, is a severe disorder of the peripheral and central nervous system myelin caused by deficient galactocerebrosidase (GALC) activity. This autosomal recessive disease affects humans and animals including dogs, mice, and rhesus monkeys. Cloning of the human and animal GALC genes opened opportunities for therapeutic trials using animal models. We describe the clinical, pathologic, and biochemical features of the affected rhesus monkey. Affected monkeys had very low GALC activity and a two base pair deletion in both copies of the GALC gene. Clinical signs of tremors, hypertonia, and incoordination led to humane euthanasia by 5 months of age. At necropsy, peripheral nerves were enlarged. Microscopically, the cerebral, cerebellar, and spinal cord white matter was infiltrated with periodic acid-Schiff-positive multinucleated globoid cells, and there was a striking lack of myelin. Peripheral nerve fibers were decreased in number and separated by Alcian blue- and safranin O-positive material. Myelin sheaths were greatly diminished. Lipid analysis of brains of 12-day-old and 158-day-old affected monkeys revealed a great excess of psychosine in white matter. The rhesus monkey model will be especially useful for exploring treatment options, including prenatal bone marrow transplantation and various approaches to gene therapy.

Correlation of major histocompatibility complex with opportunistic infections in simian immunodeficiency virus-infected rhesus monkeys.

The role of the major histocompatibility complex (MHC) in the pathogenesis of AIDS is complex because of compounding variables within the virus, host, and environment. Important variables can be controlled by using the experimental animal model of AIDS induced by simian immunodeficiency virus in rhesus monkeys (Macaca mulatta). We studied whether the MHC type influenced which opportunistic infections arose in an individual monkey. Several associations were found. For example, cytomegalovirus was strongly associated with Mamu-B6 (p < 0.001), whereas Cryptosporidium was associated strongly with Mamu-DR3 (p < 0.001). We also found that having one opportunistic infection increased the risk of having another.