RESUMO
Previous research has linked perceived social isolation (loneliness) to reduced antiviral immunity, but the immunologic effects of the objective social isolation imposed by pandemic "shelter in place" (SIP) policies is unknown. We assessed the immunologic impact of SIP by relocating 21 adult male rhesus macaques from 2,000-m2 field cage communities of 70 to 132 other macaques to 2 wk of individual housing in indoor shelters. SIP was associated with 30% to 50% reductions in all circulating immune cell populations (lymphocytes, monocytes, and granulocytes), down-regulation of Type I interferon (IFN) antiviral gene expression, and a relative up-regulation of CD16- classical monocytes. These effects emerged within the first 48 h of SIP, persisted for at least 2 wk, and abated within 4 wk of return to social housing. A subsequent round of SIP in the presence of a novel juvenile macaque showed comparable reductions in circulating immune cell populations but reversal of Type I IFN reductions and classical monocyte increases observed during individual SIP. Analyses of lymph node tissues showed parallel up-regulation of Type I IFN genes and enhanced control of viral gene expression during juvenile-partnered SIP compared to isolated SIP. These results identify a significant adverse effect of SIP social isolation on antiviral immune regulation in both circulating immune cells and lymphoid tissues, and they suggest a potential behavioral strategy for ameliorating gene regulatory impacts (but not immune cell declines) by promoting prosocial engagement during SIP.
Assuntos
Antivirais/metabolismo , Cuidadores , Interferon Tipo I/genética , Isolamento Social , Animais , Sistema Imunitário/metabolismo , Interferon Tipo I/metabolismo , Tecido Linfoide/metabolismo , Macaca mulatta , MasculinoRESUMO
The neutrophil-to-lymphocyte ratio (NLR) is a predictor of morbidity for a variety of medical conditions, but little is known about how variation in NLR arises. We examined variation in this measure in a sample of 4577 infant rhesus monkeys (54.8 % female), who participated in the BioBehavioral Assessment program at the California National Primate Research Center at 3-4 months of age. Lower values for NLR were seen for animals reared indoors, for animals that were raised to be free of specific pathogens, and for males. In addition lower NLR was associated with higher stress values of cortisol and with greater emotionality in response to an acute stressor. Finally, lower NLR in infancy was associated with greater risk for developing airways hyperresponsiveness (a hallmark of asthma); with display of diarrhea up to 3.97 years later; and with greater viral load when infected with the simian immunodeficiency virus at a mean of 6.1 years of age. Infant NLR was a better predictor of viral load than was a contemporaneously obtained measure of NLR. Infant and adult values of NLR were only modestly correlated; one reason may be that the infant measure was obtained during stressful conditions and the adult measure was obtained under baseline conditions. We propose that NLR is an integrated outcome measure reflecting organization and interaction of stress-response and immune systems. As such, assessment of NLR under conditions of stress may be a particularly useful marker of individual differences in morbidity, especially for conditions in which stress plays an important role, as in asthma, diarrhea/colitis, and AIDS.
Assuntos
Asma , Hidrocortisona , Masculino , Animais , Feminino , Macaca mulatta/fisiologia , Neutrófilos , LinfócitosRESUMO
Campylobacter is the leading cause of human gastroenteritis worldwide. Wild birds, including American crows, are abundant in urban, suburban, and agricultural settings and are likely zoonotic vectors of Campylobacter Their proximity to humans and livestock increases the potential spreading of Campylobacter via crows between the environment, livestock, and humans. However, no studies have definitively demonstrated that crows are a vector for pathogenic Campylobacter We used genomics to evaluate the zoonotic and pathogenic potential of Campylobacter from crows to other animals with 184 isolates obtained from crows, chickens, cows, sheep, goats, humans, and nonhuman primates. Whole-genome analysis uncovered two distinct clades of Campylobacter jejuni genotypes; the first contained genotypes found only in crows, while a second genotype contained "generalist" genomes that were isolated from multiple host species, including isolates implicated in human disease, primate gastroenteritis, and livestock abortion. Two major ß-lactamase genes were observed frequently in these genomes (oxa-184, 55%, and oxa-61, 29%), where oxa-184 was associated only with crows and oxa-61 was associated with generalists. Mutations in gyrA, indicative of fluoroquinolone resistance, were observed in 14% of the isolates. Tetracycline resistance (tetO) was present in 22% of the isolates, yet it occurred in 91% of the abortion isolates. Virulence genes were distributed throughout the genomes; however, cdtC alleles recapitulated the crow-only and generalist clades. A specific cdtC allele was associated with abortion in livestock and was concomitant with tetO These findings indicate that crows harboring a generalist C. jejuni genotype may act as a vector for the zoonotic transmission of Campylobacter IMPORTANCE: This study examined the link between public health and the genomic variation of Campylobacter in relation to disease in humans, primates, and livestock. Use of large-scale whole-genome sequencing enabled population-level assessment to find new genes that are linked to livestock disease. With 184 Campylobacter genomes, we assessed virulence traits, antibiotic resistance susceptibility, and the potential for zoonotic transfer to observe that there is a "generalist" genotype that may move between host species.
Assuntos
Doenças das Aves/microbiologia , Infecções por Campylobacter/microbiologia , Infecções por Campylobacter/veterinária , Campylobacter/genética , Doenças dos Primatas/microbiologia , Zoonoses/microbiologia , Animais , Animais Selvagens/microbiologia , Doenças das Aves/transmissão , Aves/microbiologia , Campylobacter/classificação , Campylobacter/isolamento & purificação , Campylobacter/fisiologia , Infecções por Campylobacter/transmissão , Bovinos , Genoma Bacteriano , Genômica , Genótipo , Humanos , Gado/microbiologia , Filogenia , Doenças dos Primatas/transmissão , Primatas/microbiologia , Ovinos , Zoonoses/transmissãoRESUMO
BACKGROUND: The worldwide increase in life expectancy has been associated with an increase in age-related morbidities. The underlying mechanisms resulting in immunosenescence are only incompletely understood. Chronic viral infections, in particular infection with human cytomegalovirus (HCMV), have been suggested as a main driver in immunosenescence. Here, we propose that rhesus macaques could serve as a relevant model to define the impact of chronic viral infections on host immunity in the aging host. We evaluated whether chronic rhesus CMV (RhCMV) infection, similar to HCMV infection in humans, would modulate normal immunological changes in the aging individual by taking advantage of the unique resource of rhesus macaques that were bred and raised to be Specific Pathogen Free (SPF-2) for distinct viruses. RESULTS: Our results demonstrate that normal age-related immunological changes in frequencies, activation, maturation, and function of peripheral blood cell lymphocytes in humans occur in a similar manner over the lifespan of rhesus macaques. The comparative analysis of age-matched SPF-2 and non-SPF macaques that were housed under identical conditions revealed distinct differences in certain immune parameters suggesting that chronic pathogen exposure modulated host immune responses. All non-SPF macaques were infected with RhCMV, suggesting that chronic RhCMV infection was a major contributor to altered immune function in non-SPF macaques, although a causative relationship was not established and outside the scope of these studies. Further, we showed that immunological differences between SPF-2 and non-SPF macaques were already apparent in adolescent macaques, potentially predisposing RhCMV-infected animals to age-related pathologies. CONCLUSIONS: Our data validate rhesus macaques as a relevant animal model to study how chronic viral infections modulate host immunity and impact immunosenescence. Comparative studies in SPF-2 and non-SPF macaques could identify important mechanisms associated with inflammaging and thereby lead to new therapies promoting healthy aging in humans.
RESUMO
Adenoviruses are DNA viruses that naturally infect many vertebrates, including humans and monkeys, and cause a wide range of clinical illnesses in humans. Infection from individual strains has conventionally been thought to be species-specific. Here we applied the Virochip, a pan-viral microarray, to identify a novel adenovirus (TMAdV, titi monkey adenovirus) as the cause of a deadly outbreak in a closed colony of New World monkeys (titi monkeys; Callicebus cupreus) at the California National Primate Research Center (CNPRC). Among 65 titi monkeys housed in a building, 23 (34%) developed upper respiratory symptoms that progressed to fulminant pneumonia and hepatitis, and 19 of 23 monkeys, or 83% of those infected, died or were humanely euthanized. Whole-genome sequencing of TMAdV revealed that this adenovirus is a new species and highly divergent, sharing <57% pairwise nucleotide identity with other adenoviruses. Cultivation of TMAdV was successful in a human A549 lung adenocarcinoma cell line, but not in primary or established monkey kidney cells. At the onset of the outbreak, the researcher in closest contact with the monkeys developed an acute respiratory illness, with symptoms persisting for 4 weeks, and had a convalescent serum sample seropositive for TMAdV. A clinically ill family member, despite having no contact with the CNPRC, also tested positive, and screening of a set of 81 random adult blood donors from the Western United States detected TMAdV-specific neutralizing antibodies in 2 individuals (2/81, or 2.5%). These findings raise the possibility of zoonotic infection by TMAdV and human-to-human transmission of the virus in the population. Given the unusually high case fatality rate from the outbreak (83%), it is unlikely that titi monkeys are the native host species for TMAdV, and the natural reservoir of the virus is still unknown. The discovery of TMAdV, a novel adenovirus with the capacity to infect both monkeys and humans, suggests that adenoviruses should be monitored closely as potential causes of cross-species outbreaks.
Assuntos
Infecções por Adenoviridae , Adenoviridae , Surtos de Doenças , Doenças dos Macacos , Pitheciidae/virologia , Pneumonia Viral , Zoonoses , Adenoviridae/genética , Adenoviridae/isolamento & purificação , Infecções por Adenoviridae/epidemiologia , Infecções por Adenoviridae/genética , Infecções por Adenoviridae/veterinária , Adulto , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Doenças dos Macacos/epidemiologia , Doenças dos Macacos/genética , Doenças dos Macacos/virologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/genética , Pneumonia Viral/veterinária , Pneumonia Viral/virologia , Zoonoses/epidemiologia , Zoonoses/transmissão , Zoonoses/virologiaRESUMO
The reverse transcriptase (RT) inhibitor tenofovir (TFV) is highly effective in the simian immunodeficiency virus (SIV) macaque model of human immunodeficiency virus infection. The current report describes extended safety and efficacy data on 32 animals that received prolonged (>or=1- to 13-year) daily subcutaneous TFV regimens. The likelihood of renal toxicity (proximal renal tubular dysfunction [PRTD]) correlated with plasma drug concentrations, which depended on the dosage regimen and age-related changes in drug clearance. Below a threshold area under the concentration-time curve for TFV in plasma of approximately 10 microg x h/ml, an exposure severalfold higher than that observed in humans treated orally with 300 mg TFV disoproxil fumarate (TDF), prolonged TFV administration was not associated with PRTD based on urinalysis, serum chemistry analyses, bone mineral density, and clinical observations. At low-dose maintenance regimens, plasma TFV concentrations and intracellular TFV diphosphate concentrations were similar to or slightly higher than those observed in TDF-treated humans. No new toxicities were identified. The available evidence does not suggest teratogenic effects of prolonged low-dose TFV treatment; by the age of 10 years, one macaque, on TFV treatment since birth, had produced three offspring that were healthy by all criteria up to the age of 5 years. Despite the presence of viral variants with a lysine-to-arginine substitution at codon 65 (K65R) of RT in all 28 SIV-infected animals, 6 animals suppressed viremia to undetectable levels for as long as 12 years of TFV monotherapy. In conclusion, these findings illustrate the safety and sustained benefits of prolonged TFV-containing regimens throughout development from infancy to adulthood, including pregnancy.
Assuntos
Fármacos Anti-HIV , Modelos Animais de Doenças , Complicações Infecciosas na Gravidez , Inibidores da Transcriptase Reversa , Síndrome de Imunodeficiência Adquirida dos Símios , Adenina/administração & dosagem , Adenina/efeitos adversos , Adenina/análogos & derivados , Adenina/farmacocinética , Adenina/uso terapêutico , Fatores Etários , Animais , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Macaca mulatta , Organofosfonatos/administração & dosagem , Organofosfonatos/efeitos adversos , Organofosfonatos/farmacocinética , Organofosfonatos/uso terapêutico , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Complicações Infecciosas na Gravidez/virologia , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/farmacocinética , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Vírus da Imunodeficiência Símia/fisiologia , Tenofovir , Fatores de Tempo , Resultado do TratamentoRESUMO
Concentric left ventricular hypertrophy (LVH) is a hallmark finding in hypertrophic cardiomyopathy that leads to diastolic dysfunction and variable cardiac consequences as severe as congestive heart failure and sudden cardiac death. LVH was diagnosed postmortem in a large colony of rhesus macaques (Macaca mulatta), but methods to screen and diagnose LVH in living animals are desired. We hypothesized that targeted echocardiography of macaques with a familial association of LVH would yield antemortem LVH diagnoses. We also hypothesized that cardiac biomarker levels would be higher in sudden-death LVH or occult LVH than controls and that cardiac troponin I (cTnI) levels would be higher in macaques housed outdoors than indoors. Sera were assayed for cardiac biomarkers (cTnI, C-reactive protein, creatinine kinase-MB, creatine phosphokinase, and LDH), in conjunction with echocardiography, after diagnosis by postmortem exam or from animals with different levels of exercise due to indoor compared with outdoor housing. None of the investigated biomarkers were associated with LVH. cTnI levels were significantly higher in serum collected from outdoor than indoor macaques. In addition, LVH was diagnosed in 29.4% of subjects with a familial association of LVH. These findings suggest that exercise may increase cTnI levels in rhesus macaques and that targeted echocardiography of rhesus macaques with a familial association of LVH was the most useful variable examined for disease surveillance.
Assuntos
Hipertrofia Ventricular Esquerda/veterinária , Macaca mulatta , Doenças dos Macacos/diagnóstico , Animais , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Creatina Quinase Forma MB/sangue , Ecocardiografia , Feminino , Hipertrofia Ventricular Esquerda/sangue , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , L-Lactato Desidrogenase/sangue , Masculino , Doenças dos Macacos/sangue , Doenças dos Macacos/diagnóstico por imagem , Troponina I/sangueRESUMO
BACKGROUND: ISATX247 is a novel calcineurin inhibitor that has shown more potency than cyclosporine in vitro. This is the first study to compare the survival times of renal allografts in nonhuman primates treated with either ISATX247 or cyclosporine. METHODS: Adult, male cynomolgus monkeys were divided into blood-group compatible and mixed-lymphocyte, stimulation-mismatched, donor-recipient pairs. Heterotopic renal transplantation and bilateral native nephrectomies were performed. The monkeys were placed into either an ISATX247 or cyclosporine treatment group. Both groups were dosed twice daily to maintain a 12-hour drug-trough level of 150 ng/mL. Whole-blood concentrations of ISATX247 and cyclosporine, complete blood counts, and serum chemistry profiles were performed three times a week. Euthanasia was performed if the serum creatinine concentration became 7 or more mg/dL or a serious complication developed. RESULTS: The group receiving ISATX247 (n=8) survived significantly (P=0.0036) longer than the group receiving cyclosporine (n=7). The mean trough blood concentration of ISATX247 was 120 +/- 32 ng/mL and cyclosporine was 189 +/- 130 ng/mL. The average area under the curve 0-12 for ISATX247 was 6045 +/- 1679 ng/mL/hr and for cyclosporine was 4919 +/- 823 ng/mL/hr. The average calcineurin inhibition at trough blood concentrations was 80 +/- 11% for ISATX247 and 48 +/- 12% for cyclosporine. CONCLUSIONS: Allografts in monkeys treated with ISATX247 survived significantly longer than those treated with cyclosporine. On the basis of survival times and degree of calcineurin inhibition, ISATX247 is a more potent immunosuppressive agent than cyclosporine in this nonhuman primate model of renal-allograft transplantation.
Assuntos
Ciclosporina/uso terapêutico , Sobrevivência de Enxerto/imunologia , Transplante de Rim/imunologia , Animais , Ciclosporina/sangue , Ciclosporina/farmacocinética , Sobrevivência de Enxerto/efeitos dos fármacos , Macaca fascicularis , Masculino , Modelos Animais , Análise de Sobrevida , Fatores de Tempo , Transplante Homólogo/imunologiaRESUMO
Simian T-lymphotropic virus type 1 (STLV-1) is a C-type retrovirus of nonhuman primates that is genetically and antigenically related to human T-lymphotropic virus type 1 (HTLV-1). Infection with STLV-1 has been reported in many species of Old World monkeys and apes, including rhesus macaques (Macaca mulatta). Similar to HTLV infection in humans, STLV infection has been associated with T-cell lymphoproliferative disease or lymphoma in a small proportion of infected animals, predominantly African species. There are conflicting reports of T-cell subset alterations in healthy HTLV-1 carriers. To the authors' knowledge, analysis of T-cell subsets in healthy STLV-1 carrier rhesus macaques has not been reported. Subsets of T cells in peripheral blood from healthy, STLV-1-seropositive rhesus macaques (n = 17) and seronegative controls matched for age and sex (n = 17) were determined by use of fluorescence-activated cell sorter analysis. Parameters measured included CD3, CD4, CD8, CD25, CD28, CD38, and HLA-DR cell sets. Significant differences in T-cell subsets or hematologic parameters were not observed between healthy STLV-seropositive and seronegative groups.
Assuntos
Infecções por Deltaretrovirus/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus Linfotrópico T Tipo 1 de Símios , Subpopulações de Linfócitos T/imunologia , Animais , Portador Sadio , Feminino , Citometria de Fluxo , Macaca mulatta , MasculinoRESUMO
Measles virus (MV), a highly infective paramyxovirus, has caused sporadic epizootics characterized by high morbidity and increased mortality in nonhuman primates. Measles vaccines for human use, although effective, are cost prohibitive for use in primate colonies. We compared the efficacy of one or two doses of Vanguard D-M, a canine distemper-measles (CD-M) vaccine, with a single dose of Attenuvax, a human measles vaccine. Compared with 81% of animals inoculated with Attenuvax, all animals inoculated with one or two doses of Vanguard developed detectable MV antibodies. One year after immunization, six juveniles from each vaccine group, along with three unvaccinated controls, were challenged with pathogenic MV and were monitored for clinical signs of disease, viremia, viral shedding, and immune response. All uninoculated controls developed clinical disease and viremia, and shed virus in nasopharangeal secretions. Subclinical viremia without viral shedding was identified in two Attenuvax- and two single-dose Vanguard-inoculated animals. Viremia was not detected in any two-dose Vanguard-inoculated animals. Significantly higher neutralization antibody titers were observed in animals receiving Vanguard. Results of this study indicate that Vanguard is at least as efficacious as Attenuvax for protection of rhesus macaques. The considerably lower cost of Vanguard makes vaccination against measles in large breeding colonies economically feasible.
Assuntos
Macaca mulatta/imunologia , Vacina contra Sarampo/imunologia , Sarampo/veterinária , Vacinação , Animais , Anticorpos Antivirais/imunologia , Formação de Anticorpos , Cinomose/imunologia , Vírus da Cinomose Canina/imunologia , Humanos , Imunidade Celular/imunologia , Sarampo/prevenção & controle , Vacina contra Sarampo/administração & dosagem , Vírus do Sarampo/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologiaRESUMO
Diarrhea is the gastrointestinal disease most frequently encountered in captive rhesus macaques. The precise pathogenic mechanisms underlying chronic diarrhea in nonhuman primates are not well understood, but a persistent inflammatory component has been implicated strongly. This study evaluated the inflammatory changes in the colon of macaques with diarrhea and assessed the efficacy of a 10-d course of tylosin in a cohort of 21 animals with chronic diarrhea. Stool quality was evaluated daily, and fecal consistency was scored. Colonoscopies were performed; biopsy samples were characterized histologically and assayed for expression of TNFalpha mRNA. Blood samples collected pre-, mid-, and post-treatment were assayed for C-reactive protein (CRP). The results indicated that 63% of the animals receiving tylosin showed improvement in stool quality, compared with 10% in the sham-treated group. Histologically, 82% of animals in the tylosin-treated group had a reduction in the severity of colonic lesions post-treatment, compared with 40% of animals in the sham group. The amount of TNFalpha mRNA before treatment did not differ from that afterward in either tylosin- or sham-treated animals. CRP levels serially decreased in tylosin-treated monkeys; the average post-treatment CRP value for tylosin-treated animals was 11.96 +/- 3.86 microg/ml compared with 26.48 +/- 4.86 microg/ml for sham-treated controls. In conclusion, tylosin significantly improved the fecal consistency score, significantly decreased colonic inflammation, and significantly decreased serum CRP levels post-treatment in rhesus macaques with chronic diarrhea.
Assuntos
Diarreia/tratamento farmacológico , Tilosina/uso terapêutico , Animais , Antibacterianos/uso terapêutico , Proteína C-Reativa/metabolismo , Doença Crônica , Colonoscopia/veterinária , Citocinas/genética , Diarreia/microbiologia , Diarreia/veterinária , Modelos Animais de Doenças , Doenças do Cão/microbiologia , Cães , Fezes/microbiologia , Regulação da Expressão Gênica , Macaca mulatta , Metronidazol/uso terapêutico , Prednisona/uso terapêutico , Doenças dos Primatas/tratamento farmacológico , Doenças dos Primatas/microbiologia , RNA Mensageiro/sangue , RNA Mensageiro/genética , Tetraciclina/uso terapêutico , Fator de Necrose Tumoral alfa/genéticaRESUMO
BACKGROUND: Exposure to environmental tobacco smoke (ETS) is associated with an increased incidence of allergic and infectious diseases among children that is thought to be partly due to the immaturity of the immune system. OBJECTIVE: We sought to investigate the effects of ETS exposure on immune development during the first year of life in the nonhuman primate. METHODS: Fifteen neonatal rhesus monkeys studied to 13 months of postnatal age were randomized into 3 groups: (1) exposure to filtered air, (2) continuous ETS exposure beginning at gestation day 50 (perinatal ETS); and (3) exposure to ETS beginning at 6 months of age (6-month ETS). Complete blood counts, lymphocyte subsets, and mRNA levels of 12 cytokines in PBMCs were measured. RESULTS: Fetal/infant exposure to ETS altered the normal maturation of mRNA levels of IFN-gamma, IL-2, and IL-10, as well as the ratio of CD4 to CD8 lymphocytes, compared with filtered-air control levels. Blood lymphocyte subset distribution also significantly differed based on the onset of exposure to ETS. Subacute exposure to ETS for 2 weeks in 6-month-old infants was found to increase levels of peripheral blood neutrophils and IL-6 mRNA. CONCLUSIONS: Short-term exposure to ETS can induce an acute systemic inflammatory response in the neonatal nonhuman primate, and long-term exposure to ETS beginning in utero or at 6 months of postnatal age can significantly alter immune effectors. CLINICAL IMPLICATIONS: Normal immune system development is compromised by in utero and postnatal exposure to ETS and might contribute to ETS-related childhood diseases.
Assuntos
Animais Recém-Nascidos/crescimento & desenvolvimento , Sistema Imunitário/embriologia , Sistema Imunitário/crescimento & desenvolvimento , Poluição por Fumaça de Tabaco , Envelhecimento/sangue , Envelhecimento/metabolismo , Animais , Citocinas/genética , Desenvolvimento Embrionário , Contagem de Leucócitos , Subpopulações de Linfócitos , Macaca mulatta , Monócitos/metabolismo , RNA Mensageiro/metabolismoRESUMO
The rhesus macaque breeding colony of the Oswaldo Cruz Foundation (FIOCRUZ) was established in 1932 from a founding stock of 100 animals. This population has remained closed to new animal introductions for almost 70 years. A serologic survey was performed to determine the prevalence of antibodies to selected viruses as a first approach to identifying viral pathogens endemic in this population. Banked serum samples were tested for antibodies to simian immunodeficiency virus (SIV), simian T-lymphotropic virus (STLV), simian type D retrovirus (SRV), cercopithecine herpesvirus type-1 (B virus), rhesus cytomegalovirus (RhCMV), measles virus (MV), and hepatitis A virus (HAV). All samples were negative for antibodies against the simian retroviruses. The overall prevalence of antibodies was 95% for RhCMV, 45% for B virus, 35% for HAV, and 1% for MV. Prevalence was found to vary by age group.
Assuntos
Anticorpos Antivirais/sangue , Macaca fascicularis/virologia , Macaca mulatta/imunologia , Macaca mulatta/virologia , Doenças dos Macacos/virologia , Animais , Betaretrovirus/isolamento & purificação , Brasil/epidemiologia , Citomegalovirus/isolamento & purificação , Feminino , Vírus da Hepatite A/isolamento & purificação , Herpesvirus Cercopitecino 1/isolamento & purificação , Masculino , Vírus do Sarampo/isolamento & purificação , Doenças dos Macacos/epidemiologia , Doenças dos Macacos/imunologia , Estudos Soroepidemiológicos , Vírus da Imunodeficiência Símia/isolamento & purificação , Vírus Linfotrópico T Tipo 1 de Símios/isolamento & purificaçãoRESUMO
The reverse transcriptase inhibitor 9-[2-(phosphonomethoxy)propyl]adenine (PMPA; tenofovir) was previously found to offer strong prophylactic and therapeutic benefits in an infant macaque model of pediatric human immunodeficiency virus (HIV) infection. We now summarize the toxicity and safety of PMPA in these studies. When a range of PMPA doses (4 to 30 mg/kg of body weight administered subcutaneously once daily) was administered to 39 infant macaques for a short period of time (range, 1 day to 12 weeks), no adverse effects on their health or growth were observed; this included a subset of 12 animals which were monitored for more than 2 years. In contrast, daily administration of a high dose of PMPA (30 mg/kg subcutaneously) for prolonged periods of time (>8 to 21 months) to 13 animals resulted in a Fanconi-like syndrome (proximal renal tubular disorder) with glucosuria, aminoaciduria, hypophosphatemia, growth restriction, bone pathology (osteomalacia), and reduced clearance of PMPA. The adverse effects were reversible or were alleviated following either complete withdrawal of PMPA treatment or reduction of the daily regimen from 30 mg/kg to 2.5 to 10 mg/kg subcutaneously. Finally, to evaluate the safety of a prolonged low-dose treatment regimen, two newborn macaques were started on a 10-mg/kg/day subcutaneous regimen; these animals are healthy and have normal bone density and growth after 5 years of daily treatment. In conclusion, our findings suggest that chronic daily administration of a high dose of PMPA results in adverse effects on kidney and bone, while short-term administration of relatively high doses and prolonged low-dose administration are safe.