Maternal transmission of type D simian retrovirus (SRV-2) in pigtailed macaques

Pregnant macaques were used as a natural model for maternal-infant transmission of SRV-2 retrovirus. Fifty-one pregnant females were placed into one of four virus/antibody groups. Nonviremic mothers produced 100% virus-negative offspring at birth. In contrast, viremic mothers produced offspring which were 17% virus-negative and 83% virus-positive at birth. SRV-2 infection occurred principally in utero by the transplacental route. Infants born to viremic mothers exhibited low birth weight, prematurity, high perinatal death, and increased incidence of SAIDS.     

Long-term protection of macaques against high-dose type D retrovirus challenge after immunization with recombinant vaccinia virus expressing envelope glycoproteins

Recombinant vaccinia virus expressing the envelope proteins of type D retrovirus-Washington (SRV-2/W) was used to immunize macaques against SRV-2 infection. Four immunized macaques which had resisted a prior low-dose challenge were rechallenged with a high dose (10” infectious particles) of SRV-2 two years after being immunized. All four non-immunized control macaques became infected, but the four vaccinated animals resisted this intravenous challenge, as determined by the inability to detect SRV-2 in peripheral blood mononuclear cells and by the lack of seroconversion to new viral antigens.     

Evidence for a lentiviral etiology in an epizootic of immune deficiency and lymphoma in stump-tailed macaques (Macaca arctoides).

A retrospective study determined that an epizootic of immune suppression and lymphoma in stump-tailed macaques (Macaca arctoides) that began in 1976 was associated with a horizontally spread lentivirus infection. This conclusion was based on serology, epidemiology, pathology, and virus isolation. The lesions found in the stump-tailed macaques were more compatible with lesions seen in SIV-infected rhesus than those seen in rhesus macaques infected with type D retroviruses. A lentivirus, isolated from a rhesus inoculated with lymph node homogenate from a stump-tailed macaque, was designed SIVstm and was pathogenic for rhesus macaques. The isolate was antigenically related to other SIVs as well as to HIV-1 and HIV-2. Two surviving stump-tailed macaques sent to another colony carried SIVstm latently for at least 7 years and disseminated it throughout that colony.     

Patterns of dominance and affiliation in wild pig-tailed macaques (Macaca nemestrina nemestrina) in West Sumatra

Patterns of agonistic and nonagonistic behaviors were studied in a troop of wild pig-tailed macaques in West Sumatra, Indonesia. The animals were provisioned and the identities of all adult and adolescent individuals were known. The females could be divided into high-, mid-, and low-ranking subsets of individuals. Most grooming occurred within, instead of between members of these subsets. The members of each subset also tended to feed together at the baiting sites, and they probably represented groups of close kin. Among females, grooming appeared to be a conciliatory behavior and was generally performed by the subordinate partner, while mounting was performed by the dominant partner and appeared to be a reassertion of dominance. High-ranking males tended to form agonistic alliances with females and to exchange grooming with estrous females. Low-ranking males did not have such associations with females and were frequently the targets of agonistic alliances of females and juveniles. Mounting between males appeared to be a conciliatory behavior. It seemed effective since severe aggression between males was not observed. The subordinate partner mounted more frequently than the dominant one, but the direction of mounting was apparently controlled by the latter. This suggests that, among pig-tailed macaques, the dominant male plays an important role in the coexistence of males in the troop.     

Maintenance of high-density lipoprotein blood levels prior to spontaneous abortion in pig-tailed macaques (Macaca nemestrina)

Blood was drawn throughout the first half of the pregnancies of 24 pig-tailed macaques (Macaca nemestrina) to evaluate longitudinal high-density lipoprotein (HDL) changes. In all 15 normal pregnancies, HDL decreased at least 50%; the mean value for the group fell from 0.45 gm/liter to 0.17 gm/liter. HDL began to fall after about four weeks of pregnancy. However, no comparable HDL change occurred in nine pregnancies that terminated in spontaneous abortions. This lack of an HDL decrease was unexpected. Subsequent studies showed that the predominant decrease was in the HDL₂ subfraction. The data indicate that the normal physiologic metabolism or utilization of HDL is aberrant early in pregnancies ending in spontaneous abortions and may be due to a dysfunctional fetal-placental unit.     

Enhanced replication of HIV-1 in vivo in pigtailed macaques (Macaca nemestrina)

Non-human primate models for acquired immunodeficiency syndrome (AIDS) are important for studies of prevention and intervention strategies. Ideally, such models would make use of human immunodeficiency virus type 1 (HIV-1) and animals that are readily available for research. HIV-1 was obtained from an infected macaque, and passaged sequentially in three groups of two Macaca nemestrina neonates each. Evidence for enhanced viral replication was first found in one of the group 2 animals, and in both group 3 animals. Observations that underlie this conclusion are sustained viral recovery from peripheral blood mononuclear cells (PBMCs), increased and accelerated production of antiviral antibodies, and the ability to detect plasma viral ribonucleic acid (RNA) months after infection. There was no evidence of CD4 depletion in any of the animals during the follow-up period. These data suggest that a useful non-human primate model for AIDS can be attained in pigtailed macaques ( M. nemestrina ).     

Characterization of T- and B-cell epitopes of a simian retrovirus (SRV-2) envelope protein.

Synthetic envelope peptides of a simian retrovirus (SRV-2) were used to define both T- and B-cell epitopes of the envelope protein. The SRV-2 peptide 100-106 specifically blocks rhesus anti-SRV-2 neutralizing antibody activity, and a peptide 100-106 keyhole limpet hemocyanin conjugate induces a strong antipeptide antibody response. SRV-2 peptide 100-106 and 233-249 induces good T-cell proliferation of murine spleen cells immunized with the SRV-2 virus. Thus, SRV-2 envelope peptide 100-106 represents both a T- and B-cell epitope, and peptide 233-249 a T-cell epitope.     

Mesenchymoproliferative disorders (MPD) in simian AIDS associated with SRV-2 infection

We have observed several mesenchymal proliferative disorders (MPD) in macaques with SAIDS associated with SRV-2 infection. Retroperitoneal and subcutaneous fibromatosis, progressive fibrovascular proliferation, mimicking Kaposi's sarcoma, were seen in 165 macaques. Three obliterative fibrointimal proliferative arteriopathies and one congenital pulmonary sequestration with extensive MPD were observed in SRV-2 positive monkeys. Continuous cell lines were established and SRV-2 was identified in all tissues and cell lines. Immunophenotyping of the cultured cells showed heterogeneous mesenchymal cells. Xenograft and allograft transplantation of cultured cells produced MPD lesions in the recipients. The data suggest that SRV-2 plays an important role in the etiopathogenesis of MPD in macaques.     

Ontogeny of locomotion in rhesus macaques (Macaca mulatta): II. Postural and locomotor behavior and habitat use in a free-ranging colony

This study quantifies changes in postural and locomotor behavior as well as habitat use across the life span of free-ranging rhesus macaques (Macaca mulatta) in the Cayo Santiago colony in Puerto Rico. It focuses on developmentally related changes from birth to adulthood, and complements an earlier study by Turnquist and Wells ([1994] J Hum Evol 26:487-499) on the early postnatal ontogeny of the musculoskeletal system of the same colony. A total of 6,551 locomotor and postural events was analyzed. Selection and use of substrate correlated well with age. The more sedentary adult and dependent infant select safe, wide, horizontal arboreal settings in contrast to the older Infant IIs and Juveniles, who are learning locomotor and postural skills through independent chase and play. Infant macaques, when independent, often employ a low center of gravity and widely abducted limbs in order to broaden their contact with the base of support. This study shows that the previously reported ontogenetic changes in morphology are closely paralleled by changes in postural and locomotor behavior, and these in turn are correlated to changes in habitat use, particularly during the formative years.     

Aspects of fight interference in free-ranging and compound-dwelling rhesus macaques (Macaca mulatta)

Patterns of fight interference (agonistic aiding) were compared among three groups of rhesus monkeys (Macaca mulatta) living in two settings: (1) two groups at Cayo Santiago (Caribbean Primate Center); and (2) one group at the Yerkes Regional Primate Research Center (YRPRC). A total of 1,227 interference episodes were recorded in 1,650 hours of observation. The only significant intergroup difference was the increased tendency of males at YRPRC to aid aggressors rather than victims. Among other findings, females aided relatives, interfered against target animals dominant to themselves, aided juveniles, and aided victims more consistently and frequently than did males. Importantly, female interference became more male-like in pattern when aid was given to nonrelatives. Neither the dominant males nor males in general displayed a unique or consistent tendency to interfere in fights in a manner which could be interpreted as controlling aggression. The males' interference patterns also did not suggest they were forming coalitions to either attain or defend status rankings. It is concluded that, overall, observations of compound-dwelling and free-ranging rhesus monkeys reveal similar relationships. Further, while female rhesus monkeys interfered in fights in a manner consistent with the control of aggression and protection of kin, the motives of male interferers remain unknown; however, their behavior is consistent with the hypothesis that they were reducing intermale tensions while, at the same time, minimizing physical risk.     

Serologic and virologic analysis of type D simian retrovirus infection in a colony of Celebes black macaques (Macaca nigra)

Celebes macaques were tested for type D simian retrovirus (SRV) infection. SRV infection was first detected in one serum sample collected during 1980. By 1983, 32 of 46 monkeys (70%) were infected. Serotyping of the SRV isolates determined that 0/26 of the isolates were SRV-1; 24/26 were SRV-2; 1/26 was SRV-5; and 1/26 could not be typed. Restriction endonuclease mapping confirmed the SRV-2C and SRV-5 isolates. In addition, two SRV-2C variants were detected.     

Growth-related shape changes in the fetal craniofacial complex of humans (Homo sapiens) and pigtailed macaques (Macaca nemestrina): a 3D-CT comparative analysis

This study investigates whether macaques and humans possess a common pattern of relative growth during the fetal period. The fetal samples consist of 16 male pigtailed macaques (mean age, 20.5 gestational weeks) and 17 humans (9 males and 8 females; mean age, 29.5 gestational weeks). For each individual, three-dimensional coordinates of 18 landmarks on the skull were collected from three-dimensional computed tomographic (CT) reconstructed images and two-dimensional CT axial slices. Early and late groups were created from the human (early mean age, 24 weeks, N = 8; late mean age, 34 weeks, N = 9) and macaque samples (early mean age, 17.7 weeks, N = 7; late mean age, 23 weeks, N = 9). Inter- and intraspecific comparisons were made between the early and late groups. To determine if macaques and humans share a common fetal pattern of relative growth, human change in shape estimated from a comparison of early and late groups was compared to the pattern estimated between early and late macaque groups. Euclidean distance matrix analysis was used in all comparisons. Intraspecific comparisons indicate that the growing fetal skull displays the greatest amount of change along mediolateral dimensions. Changes during human growth are primarily localized to the basicranium and palate, while macaques experience localized change in the midface. Interspecific comparisons indicate that the two primate species do not share a common pattern of relative growth, and the macaque pattern is characterized by increased midfacial growth relative to humans. Our results suggest that morphological differences in the craniofacial skeleton of these species are in part established by differences in fetal growth patterns.     

Enhanced infectivity of an R5-tropic simian/human immunodeficiency virus carrying human immunodeficiency virus type 1 subtype C envelope after serial passages in pig-tailed macaques (Macaca nemestrina)

The increasing prevalence of human immunodeficiency virus type 1 (HIV-1) subtype C infection worldwide calls for efforts to develop a relevant animal model for evaluating strategies against the transmission of the virus. A chimeric simian/human immunodeficiency virus (SHIV), SHIV(CHN19), was generated with a primary, non-syncytium-inducing HIV-1 subtype C envelope from a Chinese strain in the background of SHIV(33). Unlike R5-tropic SHIV(162), SHIV(CHN19) was not found to replicate in rhesus CD4(+) T lymphocytes. SHIV(CHN19) does, however, replicate in CD4(+) T lymphocytes of pig-tailed macaques (Macaca nemestrina). The observed replication competence of SHIV(CHN19) requires the full tat/rev genes and partial gp41 region derived from SHIV(33). To evaluate in vivo infectivity, SHIV(CHN19) was intravenously inoculated, at first, into two pig-tailed and two rhesus macaques. Although all four animals became infected, the virus replicated preferentially in pig-tailed macaques with an earlier plasma viral peak and a faster seroconversion. To determine whether in vivo adaptation would enhance the infectivity of SHIV(CHN19), passages were carried out serially in three groups of two pig-tailed macaques each, via intravenous blood-bone marrow transfusion. The passages greatly enhanced the infectivity of the virus as shown by the increasingly elevated viral loads during acute infection in animals with each passage. Moreover, the doubling time of plasma virus during acute infection became much shorter in passage 4 (P4) animals (0.2 day) in comparison to P1 animals (1 to 2 days). P2 to P4 animals all became seropositive around 2 to 3 weeks postinoculation and had a decline in CD4/CD8 T-cell ratio during the early phase of infection. In P4 animals, a profound depletion of CD4 T cells in the lamina propria of the jejunum was observed. Persistent plasma viremia has been found in most of the infected animals with sustained viral loads ranging from 10(3) to 10(5) per ml up to 6 months postinfection. Serial passages did not change the viral phenotype as confirmed by the persistence of the R5 tropism of SHIV(CHN19) isolated from P4 animals. In addition, the infectivity of SHIV(CHN19) in rhesus peripheral blood mononuclear cells was also increased after in vivo passages. Our data indicate that SHIV(CHN19) has adapted well to grow in macaque cells. This established R5-tropic SHIV(CHN19)/macaque model would be very useful for HIV-1 subtype C vaccine and pathogenesis studies.     

Derivation and characterization of a highly pathogenic isolate of human immunodeficiency virus type 2 that causes rapid CD4+ cell depletion in Macaca nemestrina

With few exceptions, humans are the only species known to develop acquired immunodeficiency syndrome (AIDS) after human immunodeficiency virus (HIV) infection. We report here that an isolate of HIV type 2, EHO, readily established persistent infection in 100% of Macaca nemestrina in three consecutive transmission studies. Of the eight infected animals, five showed persistently high virus load and six developed AIDS-like diseases or CD4⁺ cell depletion within 4 years of infection. The pathology and clinical signs closely parallel those of HIV-1 infection of humans, including lymphadenopathy, anemia, CD4⁺ cell depletion, and opportunistic infections. A cell-free virus stock was established from the lymph nodes of an animal that developed AIDS-like diseases. This virus, HIV-2/287, was highly pathogenic in M. nemestrina, causing CD4⁺ cell depletion within 2–8 weeks post-infection. While both HIV-2 EHO and HIV-2/287 use predominantly CXCR4, the latter shows greatly enhanced replicative capacity in macaque peripheral blood mononuclear cells (PBMCs). The establishment of a human immunodeficiency virus that causes rapid and reproducible CD4⁺ cell depletion in macaques could facilitate the study of HIV pathogenesis and the development of effective vaccines and therapy against AIDS.     

Elevated frequency of CD1c+ myeloid dendritic cells in the peripheral blood mononuclear cells of simian/human immunodeficiency virus (SHIV) and simian immunodeficiency virus (SIV) repeatedly infected Chinese rhesus macaques

CD1c+ myeloid dendritic cells (mDCs) in the peripheral blood of 30 SHIV-SF162p4 and SIVmac251 sequentially infected Chinese rhesus macaques were examined by flow cytometry to obtain further insight into mDC alterations in HIV/AIDS. The CD1c+ cells were found to be mononuclear leukocytes rather than granulocytes, and most of them expressed CD20. CD1c+mDCs (CD1c+CD20−) consisted of two morphological subsets: the granular and the large CD1c+mDCs. The expression of HLA-DR, CD86, and CD11b, but no CCR7, CD83 and CD123, together with their endocytotic capacity indicated that they were immature mDCs. Their frequency at weeks 10 and 12 post-infection was significantly higher than that of un-infected ones; the large CD1c+mDC level was significantly different between time points and almost absent from un-infected rhesus monkeys; significant correlations between CD1c+mDCs and plasma viral load levels were also observed. These data indicated a possible role for CD1c+mDCs in the pathophysiological process of SIV/HIV infection.     

D1 and D2 Dopamine Receptors in Caudate-Putamen of Nonhuman Primates (Macaca fascicularis)

D1 and D2 dopamine receptors were characterized in the caudate-putamen region of nonhuman primate brains (Macaca fascicularis). D1 dopamine receptors were identified with [3H]SCH 23390 and D2 receptors with [3H]-spiperone. Scatchard analysis of [3H]SCH 23390 saturation data using washed membranes revealed a single high-affinity binding site (KD, 0.352 +/- 0.027 nM) with a density (Bmax) of 35.7 +/- 2.68 pmol/g original wet tissue weight (n = 10). The affinity of [3H]spiperone for the D2 site was 0.039 +/- 0.007 nM and the density was 25.7 +/- 1.97 pmol/g original wet tissue weight (n = 10). D1 and D2 receptors in nonhuman primates may be differentiated on the basis of drug affinities and stereoselectivity. In competition experiments, RS-SKF 38393 was the most selective D1 agonist, whereas (+)-4-propyl-9-hydroxynaphthoxazine [(+)-PHNO] was the most selective D2 agonist. Apomorphine was essentially nonselective for D1 or D2 binding sites. Of the antagonists, R-SKF 83566 and SCH 23390 were the most selective for the D1 site, whereas YM-09151-2 was the most selective for the D2 site. cis-Flupentixol and (S)-butaclamol were the least selective dopamine antagonists. D1 receptors bound benzazepine antagonists (SCH 23390/SCH 23388, R-SKF 83692/RS-SKF 83692) stereoselectively whereas D2 receptors did not. Conversely D2 receptors bound (S)-sulpiride and (+)-PHNO more potently than their enantiomers whereas D1 receptors showed little stereoselectively for each of these isomeric pairs. These binding characteristics may be utilized for evaluation of individual receptor function in vivo.     

Retrospective case–control study of hyperglycemia in group‐housed,mature female cynomolgus macaques (Macaca fascicularis)

Background Captive cynomolgus macaques are prone to obesity, increasing their risk for developing hyperglycemia and type 2 diabetes mellitus (T2DM). Social rank may be a contributing risk factor predisposing macaques to adverse health events. Methods Using retrospective health records from 259 animals, a matched case–control study was conducted to assess risk factors for developing hyperglycemia in group‐housed, adult females aged 10 or older. Univariable exact and conditional logistic regression models were used to analyze the data. Result The odds of developing hyperglycemia were significantly greater in animals with more frequent counts of injury. Similarly, subordinate animals had higher odds of developing hyperglycemia than affiliates. Conclusions Subordinate social status may increase the risk of hyperglycemia in mature female cynomolgus macaques. Opportunities for subordinates to alter feeding strategies are reduced in captivity. This may be associated with increased social stress around feeding, and for animals housed long‐term could predispose them to obesity and hyperglycemia.     

The efficacy of orally dosed ketamine and ketamine/medetomidine compared with intramuscular ketamine in rhesus macaques (Macaca mulatta) and the effects of dosing route on haematological stress markers

BACKGROUND: This study compared the efficacy of two orally-dosed (PO) anaesthetic regimens for chemical immobilization in rhesus macaques (Macaca mulatta), versus the standard protocol of intramuscular (TM) ketamine. In addition, the effects of dosing route on haematological stress markers were evaluated. METHODS: Testing was conducted on 18 chronically housed animals. Animals were trained to accept oral dosing and then randomly assigned to one of three drug regimens: (1) ketamine IM, (2) ketamine PO, (3) Ketamine/medetomidine PO. Sedation levels for each regimen were evaluated. RESULTS: Oral dosing alone was not sufficient to achieve a plane of sedation that allowed for safe handling. Serum cortisol and glucose levels were unchanged across groups, although differences were observed in the leukogram profiles. CONCLUSION: The oral dosages used in this study fell short in providing adequate sedation for safe handling for routine veterinary procedures. Leukogram profiles indicated that orally dosed animals experienced a higher level of stress.