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Biomedical subjects

H M McClure

Publications and source records attributed to H M McClure.

At least 19 recordsLinked to original sources
PubMed1995

The proteins of lymphocyte- and macrophage-tropic strains of simian immunodeficiency virus are processed differently in macrophages.

Since the pathogenesis of SIVmac disease complex is thought to be explained by the tropism of the infecting virus for either CD4+ T-lymphocytes or macrophages or both types of cells, we compared the infection in primary macaque macrophages with molecularly cloned, lymphocyte-tropic SIVmac239 and a cloned, macrophage-tropic chimeric virus (SIVmac239/17E) whose env gene was derived from brain of a macaque (17E) dying from SIV-induced encephalopathy. SIVmac239/17E caused a productive, syncytial cytopathic infection accompanied by accumulation of virus particles within cytoplasmic vesicles of the macrophages. Pulse-chase and immune precipitation studies showed that both the viral glycoprotein precursor (gp160) and the gag precursor (p57) were cleaved into gp120 and p27, respectively, and both were released into the culture medium of infected cells, although most of the p27 remained cell associated. SIVmac239 also infected macrophages, but in comparison to SIVmac239/17E, minimal virus replication occurred. Immunocytostaining revealed that while occasional syncytia were observed in cultures, the majority of the infected cells were not associated with syncytium formation. Ultrastructural studies did not reveal the accumulation of virions within infected macrophages. Pulse-chase studies showed that both gp160 and p57 were produced but were cleaved inefficiently and only minimal amounts of gp120 and p27 were released into the culture medium, even after prolonged incubation times. The processing of proteins of the two viruses was indistinguishable in lymphocytes. Since these two viruses are identical except for changes within the env gene, these results indicate that efficient assembly and release of SIV from blood-derived macrophages is mediated by changes in the envelope glycoprotein.

Animals↗
PubMed1995

Effects of 5-benzylacyclouridine, an inhibitor of uridine phosphorylase, on the pharmacokinetics of uridine in rhesus monkeys: implications for chemotherapy.

The effects of subcutaneous administration of 5-benzylacyclouridine (BAU), a uridine phosphorylase (UrdPase, EC 2.4.2.3) inhibitor, on uridine concentration in plasma and urine were evaluated in rhesus monkeys. Administration of BAU at 50, 100 and 250 mg/kg increased the plasma uridine baseline concentration 1.5-, 2.9-, and 3.2-fold, respectively. The basis for this moderate perturbation of plasma uridine by BAU was investigated using a tracer dose of 500 microCi 3H-uridine. Administration of 3H-uridine alone led to its rapid catabolism to uracil and dihydrouracil. Administration of 83.3 mg/kg BAU with 500 microCi 3H-uridine resulted in a 2.5-fold enhancement of 3H-uridine plasma levels and a substantial decrease in the plasma levels of uridine catabolites, suggesting inhibition of UrdPase activity by BAU in rhesus monkeys. Coadministration of 83.3 mg/kg BAU with 83.3 mg/kg uridine also reduced the plasma concentration of uracil and dihydrouracil, but it did not increase plasma uridine concentration above that of control animals receiving 83.3 mg/kg uridine alone. In animals receiving uridine alone at 83.3 or 25 mg/kg, approximately 10% of the administered dose was recovered in the urine within 6 h, with unchanged uridine being the major component. In contrast, administration of 83.3 mg/kg BAU increased the excretion of unchanged uridine to more than 32% of the total dose administered, even when the urinary excretion ratio of uracil to uridine was reduced ten-fold. Administration of multiple doses (three times per day) of BAU alone (83.3 mg/kg) or in the presence of uridine (83.3 mg/kg) did not enhance plasma uridine concentration further. In addition, uridine pharmacokinetics were associated with a time-dependent relationship as evidenced by an increased total plasma clearance, renal clearance and volume of distribution, resulting in a substantial decrease in uridine peak concentration with time. These results indicate that administration of BAU inhibits UrdPase activity in rhesus monkeys as manifested by decreased uracil and dihydrouracil plasma levels, as well as a lower urinary excretion ratio of uracil to uridine, as compared to control animals. However, plasma levels of unchanged uridine were not substantially enhanced by BAU in spite of the large increase in urinary excretion of unchanged uridine. This phenomenon was also observed when uridine was coadministered with BAU, suggesting that plasma uridine concentration in monkeys may be strongly regulated by the renal system as evidenced by the "spillover" of excess plasma uridine into urine. In addition, the pharmacokinetics of uridine were dose-independent, but time-dependent.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Experimental leprosy in monkeys. I. Sooty mangabey monkeys: transmission, susceptibility, clinical and pathological findings.

A total of 31 sooty mangabey monkeys (SMM) (Cercocebus torquatus atys) inoculated by various routes with differing numbers of SMM-origin Mycobacterium leprae (ML) and 4 SMM inoculated with human-origin ML were observed for 4-12 years. SMM-origin ML was more pathogenic in SMM than human-origin ML. The spectrum of disease ranged from indeterminate to borderline and lepromatous in different animals. Some animals developed pure neural leprosy. Erythema nodosum leprosum (SNL) was also observed. Combined intravenous/intracutaneous (IV/IC) routes of inoculation more effectively induced advancing, disseminated lepromatous forms of leprosy; IV or IC routes alone were less effective at comparable doses. Total IV/IC doses of SMM-origin ML equal to or greater than 5 x 10(8), with morphologic indices (MIs) ranging from 5 to 10%, produced advancing, disseminated LL leprosy in 92% of SMM. Lower IV/IC doses and inoculations by a single IV or IC route produced fewer leprosy infections and more spontaneous regressions. As a species, captive SMM are highly susceptible to experimental leprosy and provide an excellent model for the longitudinal study of leprosy.

Animals↗
PubMed1994

Effect of recombinant human interleukin-6 (rhIL-6) and rhIL-3 on hematopoietic regeneration as demonstrated in a nonhuman primate chemotherapy model.

Using a recently developed hepsulfam-induced pancytopenia model in rhesus macaques, we have studied the effects of recombinant human interleukin-6 (rhIL-6) and rhIL-3 on marrow regeneration. Control animals were given hepsulfam (1.5 g/m2 by a single 30-minute intravenous [i.v.] injection, n = 4), while study animals received hepsulfam followed by rhIL-6, rhIL-3, or a combination of rhIL-6 and rhIL-3 (n = 3 per study group). Each cytokine was administered by once-daily subcutaneous (SC) injection (15 micrograms/kg/d) for 3 weeks beginning the day after chemotherapy (days 2 through 22). Mean platelet counts in control animals were < 100,000/microL on days 15 through 24, with 50% of the counts < 50,000/microL and two of four animals requiring platelet transfusion. In the rhIL-6- and rhIL-6/rhIL-3-treated groups, the nadir mean platelet counts were 164,000 +/- 58,700/microL and 162,300 +/- 23,800/microL, respectively, and occurred on day 15. Platelet counts in the rhIL-3-treated group were similar to those in controls. Mean absolute neutrophil counts (ANCs) < 1,000/microL occurred on days 10 through 29 in control animals, days 8 through 15 in rhIL-6-treated animals, and days 6 through 8 and 13 in rhIL-6/rhIL-3-treated animals. The frequency of ANCs < 500/microL was significantly less in the rhIL-6- and rhIL-6/rhIL-3-treated groups versus control groups (2.7 +/- 0.6 and 2.0 +/- 1.0 vs 7.0 +/- 1.4 occurrences, respectively; P < .05). rhIL-3-treated animals had ANCs similar to those in controls; one animal died with septicemia on day 21. Monkeys receiving rhIL-6 were significantly more anemic during the cytokine administration period; however, the anemia resolved by day 24. Coadministration of rhIL-3 and rhIL-6 partially corrected the anemia. The data indicate that rhIL-6 prevents significant thrombocytopenia and shortens the neutropenic period in this chemotherapy model.

Animals↗
PubMed1994

Effect of a preferred companion in modulating stress in adult female rhesus monkeys.

Using a counterbalanced design, seven adult female rhesus monkeys were removed from their social group and housed in a novel environment both alone and with a companion chosen on the basis of quantitative affiliative behaviors. Blood samples (n = 2) were collected from all study animals before the exposure to the novel environment, then at 2, 24, and 96 h thereafter for cortisol and immunological analyses. During both conditions, subjects showed evidence of stress as indicated by elevated cortisol concentrations and decreases in absolute numbers of lymphocyte subsets. There was no significant interaction between condition (alone vs. companion) and time in cortisol percent change and further planned post hoc analyses showed no significant between-condition differences for any of the postseparation time points. Similarly, no significant interaction was found between conditions and time for the absolute number of CD4+CD8-T cells, CD8+CD4- T cells, or CD20+CD2- B cells. However, planned post hoc comparisons showed that subjects in the companion condition exhibited a significantly smaller percent change from baseline than in the alone condition at the 24 h and 96 h sample periods in absolute numbers of CD4+CD8- and CD8+CD4- T cells. Results showed that adult female rhesus monkeys exhibited a profound stress response when removed from their social group to a novel environment and that recovery time of T cell subsets was significantly enhanced by the presence of a preferred companion.

Animals↗
PubMed1994

Simian immunodeficiency virus SIVsmmPBj 1.9 induces multinucleated giant cell formation in human peripheral blood monocytes.

SIVsmmPBJ 1.9 is an extremely virulent clone of the simian immunodeficiency virus SIVsmmPBj 14 that causes an acute lethal disease in pigtail macaques, with death occurring 6 to 8 days after infection. The disease is characterized by bloody mucoid diarrhea, lymphoid hyperplasia, and giant cell pneumonia. We have developed an in vitro model for the production of multinucleated giant cells (MGCs) in which peripheral blood monocytes rapidly fuse to form MGCs when cultured in lymphocyte-conditioned medium and antibody against class II MHC. We have tested the effect of SIVsmmPBj on monocytes in our MGC model system. Peripheral blood mononuclear cells (PBMCs) from normal healthy human subjects, when cultured in the presence of anti-class II MHC monoclonal antibody and SIVsmmPBj 1.9, but not either alone, resulted in the formation of MGCs within 4 days. Experiments using Transwell chambers indicated that such MGCs are formed by fusion of monocytes, not by virus-induced fusion of lymphocytes. SIVsmmPBj 1.9 is unique in inducing MGC formation in that other SIV and HIV isolates do not induce MGCs. Whereas SIVsmmPBj 1.9 grown in PBMCs was a potent inducer of MGCs in the presence of anti-class II MHC antibody, SIVsmmPBj 1.9 grown in CEMx174 failed to do so. Antibodies against IFN-gamma and TNF-alpha significantly inhibited SIVsmmPBj/anti-class II-induced formation of MGCs. These results indicate that cytokines released in response to SIVsmmPBj 1.9, in conjunction with antibodies to class II MHC, caused fusion of monocytes.

Cell Division↗
PubMed1994

Neonatal treatment with luteinizing hormone-releasing hormone analogs alters peripheral lymphocyte subsets and cellular and humorally mediated immune responses in juvenile and adult male monkeys.

We examined the effect of treatment with a LH-releasing hormone (LHRH) agonist (Ag), antagonist (Ant), or Ant and androgen (Ant/And) for the first 4 months of postnatal life on lymphocyte subsets and cellular and humorally mediated immune responses in juvenile and adult male monkeys. We also determined the effect of 9 weeks of Ant treatment on lymphocyte subsets in adult male monkeys. Adult male monkeys that had been treated neonatally with an Ag had increased levels of CD8-positive (CD8+) T-cells and reduced levels of B-cells compared to vehicle-treated controls. Lymphocytes from these animals also showed an elevated proliferative response to a variety of mitogens compared to cells from control animals. Antibody production in response to tetanus toxoid was normal in treated animals. Other neonates treated with Ant/And exhibited subnormal levels of lymphocytes, CD8+ T-cells, and B-cells at 4 months of age. Similar changes, but of lesser magnitude, were observed in animals treated with Ant alone. At 6 months of age, lymphocytes from both groups of Ant-treated monkeys exhibited an above normal proliferative response to streptolysin-O, but not to other mitogens. At 18 months of age, animals treated with Ant alone produced more antitetanus antibody in response to a tetanus toxoid booster than the controls or Ant/And-treated animals. Ant treatment was without major effect on lymphocyte subsets in adult monkeys. Serum LH and testosterone levels declined, and there was a small but significant increase in B-cells, lymphocytes expressing the interleukin-2 receptor, and the CD4+/CD8+ T-cell ratio during treatment, but these parameters normalized during the posttreatment period. The data suggest that chronic neonatal treatment with an Ag or Ant alters the development of immune system responses in male primates. The significance of these changes and their impact on the ability of these animals to respond to pathogenic agents is under investigation.

Aging↗
PubMed1994

Encephalomyelitis due to a Sarcocystis neurona-like protozoan in a rhesus monkey (Macaca mulatta) infected with simian immunodeficiency virus.

A captive-born rhesus monkey (Macaca mulatta) experimentally infected with simian immunodeficiency virus developed neurologic abnormalities approximately seven months postinoculation. A chronic necrotizing encephalomyelitis with intralesional protozoal schizonts was diagnosed histologically. The protozoa was identified as Sarcocystis neurona based on its morphologic characteristics by light and electron microscopic examination, the developmental stages of the schizonts, and positive staining with antisera against Sarcocystis cruzi by immunocytochemical techniques. Although S. neurona may be confused with Toxoplasma gondii by light microscopy, the former lacks rhoptries, is in direct contact with the host cell cytoplasm, and divides by endopolygeny. Sarcocystis neurona has recently been identified as an etiologic agent of encephalomyelitis in horses, raccoons, and mink.

Animals↗
PubMed1993

CD34+ and CFU-GM progenitors are significantly decreased in SIVsmm9 infected rhesus macaques with minimal evidence of direct viral infection by polymerase chain reaction.

Hematologic abnormalities in the peripheral blood and bone marrow are associated with human immunodeficiency and simian immunodeficiency virus (HIV, SIV) infection. The reasons for these abnormalities remain unclear. Bone marrow specimens collected from uninfected animals (Group A, Controls) and from rhesus macaques experimentally infected with SIVsmm9 during the asymptomatic stage (Group B, SIV+ "well") and during the clinically ill stage (Group C, SIV+ "sick"), underwent a variety of in vitro assays of hematopoiesis. Colony forming unit-granulocyte/macrophage (CFU-GM) per plate growth was 46.7 +/- 7.7, 31.9 +/- 8.4 and 6.5 +/- 5.0 (mean +/- sd, P < .02 each mean compared to the others) in the 3 groups respectively. Burst forming unit-erythroid (BFU-E) growth was similarly decreased in bone marrow samples from the SIV+ animals. There was no change in the number of CFU-GM per plate with the removal of plastic adherent or T-cell mononuclear cell fractions. There was no increase in CFU-GM per plate growth with the addition of low dose GM-CSF (1 or 5 ng/mL) though there was a near 67% increase (48 to 80 CFU-GM per plate) with the addition of 100 ng/mL recombinant rhesus IL-3 and 100 ng/mL GM-CSF in SIV+ "sick" animals. Variation in frequency of CD34+ progenitor cells in SIV+ animals was seen, with 3.0% CD34+ cells in SIV- controls, 4.9% CD34+ cells in SIV+ "well" animals and 0.5% CD34+ progenitor cells in SIV+ "sick" monkeys (P < .01, each mean compared to the others). Finally, there was minimal evidence of SIV sequences by polymerase chain reaction in pooled cultured CFU-GM, and no evidence in flowcytometrically sorted CD34+ progenitor cells from selected animals. Thus, the SIV seropositive rhesus monkey appears to have similar hematopoietic aberrations as are found in HIV infected human subjects and may be an excellent model for studying the interaction of lentiviruses on the kinetics of blood formation.

Animals↗
PubMed1993

In vitro and in vivo disposition and metabolism of 3'-deoxy-2',3'-didehydrothymidine.

The disposition and metabolic fate of 3'-deoxy-2',3'-didehydrothymidine (D4T) were evaluated both in isolated hepatocytes and in nonhuman primates. Rapid formation of thymine and beta-aminoisobutyric acid (BAIBA) occurred following incubation of hepatocytes with 10 microM [5(-3)H]D4T. Substantial levels of tritiated water were also detected. Exposure of cells to D4T in the presence of either 1 mM thymine or 10 microM benzyloxybenzyluracil, an inhibitor of dihydropyrimidine dehydrogenase, decreased intracellular BAIBA levels by approximately 89 and 63%, respectively. Concurrently, [3H]thymine levels increased two- to fivefold. These results are consistent with D4T being cleaved to thymine, which is then degraded to BAIBA. A similar metabolic disposition was observed in monkeys following administration of 25 mg of [5(-3)H]D4T per kg of body weight. BAIBA, thymine, and tritiated water were identified in plasma and urine. Approximately 50% of the administered dose was recovered in urine within 24 h, with the majority of the radioactivity representing unchanged drug. After administration intravenously or orally of 25 mg of [4(-14)C]D4T per kg of body weight to monkeys, a novel metabolite, designated X, in addition to unchanged D4T, thymine, and BAIBA, was also detected. The sum of the three metabolites and unchanged drug accounted for virtually all of the radioactivity in plasma and urine. Thymine and X exhibited kinetic profiles similar to that of D4T, with plasma elimination half-life of 2 to 3 h, whereas BAIBA levels remained constant for extended periods and declined slowly; this metabolite could be detected 24 h after intravenous drug administration. Mean oral bioavailability of D4T was high at approximately 70%. As observed in the [5(-3)H]D4T study performed in monkeys, approximately half of the administered [4(-14)C]D4T was recovered unchanged. The remainder was not recovered in urine or feces collected up to 30 days after drug administration. These data suggest that D4T metabolites are further metabolized by salvage pathways and/or converted to biological macromolecules.

Aminoisobutyric Acids↗
PubMed1993

Multifactorial etiology of anemia in SIV-infected rhesus macaques: decreased BFU-E formation, serologic evidence of autoimmune hemolysis, and an exuberant erythropoietin response.

We attempted to define the etiology of anemia in SIV-infected rhesus macaques. Bone marrow culture showed significantly decreased (75% reduction) burst forming unit-erythroid (BFU-E) growth in end-stage SIV+ "sick" animals. Direct antiglobulin tests (DAT) were positive in nine of 35 SIV+ "well" and 14 of 14 SIV+ "sick" monkeys (0 of 25 control animals had positive DATs). In animals with a positive DAT, moderate to severe anemia was observed, as was increased LDH and spherocytosis. Erythropoietin was measured in four control, eight SIV+ "well" and five SIV+ "sick" animals with mean levels of 4.0, 15.4, and 1176 mU/mL (r = .94) in the three groups. These data suggest that the cause of anemia in the SIV-infected rhesus macaque is multifactorial, that there may be a defect in erythropoiesis, and that, serologically, an IgG mediated autoimmune hemolytic anemia is also present.

Anemia↗
PubMed1993

Spermatogenesis and hormone levels in rhesus macaques inoculated with simian immunodeficiency virus.

The presence of sperm in testicular tissue of rhesus macaques that died as a result of infection with simian immunodeficiency virus (SIV) was related to age and body weight. Depressed testosterone levels were not associated with elevated LH levels. The data suggest that azoospermia in the SIV-infected macaques was due to cachexia and not a direct effect of virus on the testis, supporting a similar hypothesis regarding azoospermia in men infected with human immunodeficiency virus.

Age Factors↗
PubMed1992

Behavioral and physiological response of juvenile sooty mangabeys to reunion with their mothers following a year's absence.

The return of 6 juvenile mangabey monkeys to their social group following an absence of a year resulted in increased basal cortisol secretion for both the offspring and the mothers and in significant decrements in the absolute number of lymphocyte subsets for the offspring. Six 9-month-old sooty mangabeys were removed from their socially housed mothers, subsequently peer housed, and returned to the maternal social group 1 year later. Offspring showed a significant increase in cortisol levels 24 hr following reunion (48 +/- 6%) and this difference persisted through 1 month, while the mothers showed a significant increase only at the 24-hr sample point (18 +/- 3%). Moreover, the offspring, but not the mothers, showed a significant decrease in lymphocyte subsets which were evident through the 1-month sample point. Behavioral data revealed a significant positive correlation between the percent of total scan samples offspring were with their mothers (proximity, contact, huddle) the day of return and the offspring's percent change from baseline in total T cells 24 hr later, r = 0.84. All mother-offspring pairs with the exception of one exhibited frequent affiliative behaviors toward one another by 6 days following the return. These data demonstrate that the reunion of juvenile mangabeys with their mothers after a year's absence is an acute stressor for the mothers and a relatively longer term stressor for the offspring, and that behavioral interactions which characterize the return of individual subjects to the natal group can predict acute physiological responses.

Animals↗
PubMed1992

Social separation and reunion affects immune system in juvenile rhesus monkeys.

Removal of juvenile rhesus monkeys from their natal social group to indoor individual caging resulted in increased basal cortisol secretion and significant decrements in the frequency of lymphoid subpopulations. Fourteen juvenile rhesus monkeys, which had never been removed from the group, were studied. Baseline immune and cortisol measurements were obtained before seven of the subjects were removed from social housing to standard individual cages. The remaining seven subjects, matched for age, sex, weight, and rank, remained in the social group throughout the study serving as controls. Blood samples were taken 24 hours after removal of the test subjects from the group and at specific intervals thereafter through 11 weeks. At 24 hours after the separation test subjects showed a significant increase in basal cortisol levels (40%) and a significant decrease in several immune parameters, with absolute numbers of total T cells declining 72 +/- 12%. Significant group differences in immune parameters persisted through 11 weeks. Eighteen weeks following removal, the test subjects were returned to the group which produced a cortisol rise in both test and controls at the 24-hour postreturn sample. Although there were no group differences in the frequency of lymphoid subsets 24 hours after return, some test subjects showed marked decrements which were inversely related to cortisol and were predicted by behavioral events. These data demonstrate that the removal of naive juvenile rhesus monkeys from their natal social group to individual indoor caging is a potent psychosocial stressor and that the behavioral interactions which characterize the return of the individual subjects to the natal group may predict physiological response.

Animals↗
PubMed1992

SIV from stump-tailed macaques: molecular characterization of a highly transmissible primate lentivirus.

Over the past 6 years, simian immunodeficiency viruses (SIVs) have been isolated from four distinct species of macaques (Macaca mulatta, M. fascicularis, M. nemestrina, and M. arctoides) in captivity in the United States. However, the epidemiologic and genetic relationships among SIVs from the four species are not well understood. SIV from stump-tailed macaques (M. arctoides) (SIVstm) is unusual in that it has been associated with outbreaks of infection characterized by aggressive spread within stump-tailed macaque colonies at two separate primate centers in the United States. To characterize SIVstm at the molecular level, we have derived six biologically active viral DNA clones by polymerase chain reaction amplification of genomic DNA from infected cells. Nucleotide sequence analyses of one clone (SIVstm/37.16) showed that SIVstm was indeed a member of the previously defined group of simian lentiviruses that are closely related to the human immunodeficiency virus type 2 (HIV-2). However, our data indicate that SIVstm is equidistantly related to the other SIVs from macaques (SIVmac 251/142 and SIVmne) and SIV from African sooty mangabeys (SIVsmm). These findings suggest that SIV from captive macaques may have originated from several cross-species transmissions from imported sooty mangabeys and that additional spread has been fostered by the exchange of macaques among primate centers.

Amino Acid Sequence↗