RESUMEN
Transmission of HIV-1 to newborns and infants remains high, with 130,000 new infections in 2022 in resource poor settings. Half of HIV-infected newborns, if untreated, progress to disease and death within 2 years. While immunologic immaturity likely promotes pathogenesis and poor viral control, little is known about immune damage in newborns and infants. Here we examined pathologic, virologic, and immunologic outcomes in rhesus macaques exposed to pathogenic SHIV at 1-2 weeks, defined as newborns, or at 4 months of age, considered infants. Kinetics of plasma viremia and lymph node seeding DNA were indistinguishable in newborns and infants, but levels of viral DNA in gut and lymphoid tissues 6-10 weeks post-infection were significantly higher in newborns versus either infant or adult macques. Two of six newborns with the highest viral seeding required euthanasia at 25 days. We observed age-dependent alterations in leukocyte subsets and gene expression. Compared with infants, newborns had stronger skewing of monocytes and CD8+ T cells toward differentiated subsets and little evidence of type I interferon responses by transcriptomic analyses. Thus, SHIV infection reveals distinct immunological alterations in newborn and infant macaques. These studies lay the groundwork for understanding how immune maturation affects pathogenesis in pediatric HIV-1 infection.
RESUMEN
Yellow fever virus (YFV) is endemic in >40 countries and causes viscerotropic disease with up to 20%-60% mortality. Successful live-attenuated yellow fever (YF) vaccines were developed in the mid-1930s, but their use is restricted or formally contraindicated in vulnerable populations including infants, the elderly, and people with compromised immune systems. In these studies, we describe the development of a next-generation hydrogen peroxide-inactivated YF vaccine and determine immune correlates of protection based on log neutralizing index (LNI) and neutralizing titer-50% (NT50) studies. In addition, we compare neutralizing antibody responses and protective efficacy of hydrogen peroxide-inactivated YF vaccine candidates to live-attenuated YFV-17D (YF-VAX) in a rhesus macaque model of viscerotropic YF. Our results indicate that an optimized, inactivated YF vaccine elicits protective antibody responses that prevent viral dissemination and lethal infection in rhesus macaques and may be a suitable alternative for vaccinating vulnerable populations who are not eligible to receive replicating live-attenuated YF vaccines.
Asunto(s)
Anticuerpos Neutralizantes , Anticuerpos Antivirales , Modelos Animales de Enfermedad , Peróxido de Hidrógeno , Macaca mulatta , Vacunas de Productos Inactivados , Vacuna contra la Fiebre Amarilla , Fiebre Amarilla , Virus de la Fiebre Amarilla , Animales , Vacunas de Productos Inactivados/inmunología , Vacuna contra la Fiebre Amarilla/inmunología , Fiebre Amarilla/prevención & control , Fiebre Amarilla/inmunología , Virus de la Fiebre Amarilla/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Vacunas Atenuadas/inmunología , Chlorocebus aethiops , Células Vero , HumanosRESUMEN
Passively administered monoclonal antibodies (mAbs) given before or after viral infection can prevent or blunt disease. Here, we examine the efficacy of aerosol mAb delivery to prevent infection and disease in rhesus macaques inoculated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant via intranasal and intratracheal routes. SARS-CoV-2 human mAbs or a human mAb directed to respiratory syncytial virus (RSV) are nebulized and delivered using positive airflow via facemask to sedated macaques pre- and post-infection. Nebulized human mAbs are detectable in nasal, oropharyngeal, and bronchoalveolar lavage (BAL) samples. SARS-CoV-2 mAb treatment significantly reduces levels of SARS-CoV-2 viral RNA and infectious virus in the upper and lower respiratory tracts relative to controls. Reductions in lung and BAL virus levels correspond to reduced BAL inflammatory cytokines and lung pathology. Aerosolized antibody therapy for SARS-CoV-2 could be effective for reducing viral burden and limiting disease severity.
Asunto(s)
COVID-19 , SARS-CoV-2 , Animales , Humanos , Macaca mulatta , COVID-19/patología , Aerosoles y Gotitas Respiratorias , Pulmón/patología , Anticuerpos Antivirales , Replicación Viral , Anticuerpos MonoclonalesRESUMEN
Allogeneic hematopoietic stem cell transplantation (alloHSCT) from donors lacking C-C chemokine receptor 5 (CCR5Δ32/Δ32) can cure HIV, yet mechanisms remain speculative. To define how alloHSCT mediates HIV cure, we performed MHC-matched alloHSCT in SIV+, anti-retroviral therapy (ART)-suppressed Mauritian cynomolgus macaques (MCMs) and demonstrated that allogeneic immunity was the major driver of reservoir clearance, occurring first in peripheral blood, then peripheral lymph nodes, and finally in mesenteric lymph nodes draining the gastrointestinal tract. While allogeneic immunity could extirpate the latent viral reservoir and did so in two alloHSCT-recipient MCMs that remained aviremic >2.5 years after stopping ART, in other cases, it was insufficient without protection of engrafting cells afforded by CCR5-deficiency, as CCR5-tropic virus spread to donor CD4+ T cells despite full ART suppression. These data demonstrate the individual contributions of allogeneic immunity and CCR5 deficiency to HIV cure and support defining targets of alloimmunity for curative strategies independent of HSCT.
Asunto(s)
Infecciones por VIH , Trasplante de Células Madre Hematopoyéticas , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Animales , Macaca fascicularis , Carga ViralRESUMEN
Papillomaviruses (PVs) are a diverse group of host species-specific DNA viruses, etiologically linked with various benign and malignant neoplasms of cutaneous and mucosal epithelia. Here, we describe the detection and characterization of the first two PVs naturally infecting Japanese macaques (Macaca fuscata), including the determination of their etiological association(s) with the development of original neoplasms. The molecular and phylogenetic analyses were performed on complete genome sequences of Macaca fuscata PV types 1 (MfuPV1) and 2 (MfuPV2), which were completely sequenced in samples of a malignant oral tumor and benign anogenital neoplasm of Japanese macaques, respectively. Subsequently, two type-specific quantitative real-time PCRs were developed to estimate viral loads of MfuPV1 and MfuPV2 and to evaluate their etiological roles. The in silico molecular analyses revealed that both viral genomes encode characteristic PV proteins with conserved functional domains and have a non-coding genomic region with regulatory sequences to regulate and complete the viral life cycle. However, additional experimental evidence is needed to finally confirm the presence and biological functionality of the molecular features of both novel PVs. While MfuPV1, together with PVs identified in other macaques, is classified into the Alphapapillomavirus (Alpha-PV) species 12, MfuPV2 is most likely a representative of the novel viral species within the Alpha-PV genus. Their relatively high viral loads suggest that both PVs are etiologically linked with the development of the original neoplasms.
Asunto(s)
Neoplasias del Ano/veterinaria , Neoplasias de los Genitales Femeninos/veterinaria , Neoplasias de los Genitales Masculinos/veterinaria , Macaca fuscata/virología , Neoplasias de la Boca/veterinaria , Neoplasias/veterinaria , Papillomaviridae/clasificación , Papillomaviridae/genética , Infecciones por Papillomavirus/veterinaria , Animales , Neoplasias del Ano/virología , Secuencia de Bases , Femenino , Neoplasias de los Genitales Femeninos/virología , Neoplasias de los Genitales Masculinos/virología , Genoma Viral , Masculino , Boca/virología , Neoplasias de la Boca/virología , Neoplasias/virología , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/virología , Filogenia , Carga ViralRESUMEN
Subcutaneous injection site reactions to sustained-release buprenorphine hydrochloride (Buprenorphine SR) in macaques have been reported in only a single case report. In the current study, we evaluated the incidence rate and predictors of buprenorphine SR reactions in the subcutaneous tissue of rhesus macaques (Macaca mulatta) based on retrospective review of macaque buprenorphine SR injection records. Potentially predictive variables were identified with logistic regression modeling and were evaluated using model selection based on Akaike information criterion. Record review revealed sub- cutaneous tissue reactions occurred in 52 (3%) of 1559 injections and were noted between 4 and 311 d after injection. Model selection showed that body weight and MHC allele Mamu-B*29 were the best predictors of subcutaneous reactions. Based on these results, we recommend consideration of potential risk factors prior to the administration of buprenorphine SR to a rhesus macaque. In addition, the authors advise that using the highest concentration of buprenorphine SR available may reduce injection site reaction rates due to the injection of less copolymer.
Asunto(s)
Buprenorfina , Animales , Buprenorfina/efectos adversos , Preparaciones de Acción Retardada , Humanos , Reacción en el Punto de Inyección , Macaca mulatta , Estudios Retrospectivos , Tejido SubcutáneoRESUMEN
Tumors of urinary origin are infrequently reported in non-human primates. Urothelial carcinoma involving the urinary bladder was diagnosed in an adult female Japanese macaque that extended transmurally to the uterus and cervix. To our knowledge, this is the first report of a primary cystic urothelial carcinoma in a Japanese macaque.
Asunto(s)
Carcinoma de Células Transicionales/diagnóstico , Macaca fuscata , Enfermedades de los Monos/diagnóstico , Neoplasias de la Vejiga Urinaria/diagnóstico , Animales , Carcinoma de Células Transicionales/patología , Cuello del Útero/patología , Femenino , Enfermedades de los Monos/patología , Neoplasias de la Vejiga Urinaria/patología , Urotelio/patología , Útero/patologíaRESUMEN
Epidermolysis bullosa simplex (EBS) is an inherited skin disorder characterized by increased skin and mucous membrane fragility. Most cases are caused by mutations in keratin 5 (KRT5) and keratin 14 (KRT14). Mutations of these genes result in cytoskeletal disruption of the basal keratinocytes. Gross and histopathologic findings of 2 clinically affected homozygous rhesus macaques with an insertion variant mutation in KRT5 are described and compared with 6 deceased phenotypically normal animals that were heterozygous for the KRT5 insertion variant. Animals that were homozygous for the KRT5 insertion variant were stillborn and had widespread loss of the epidermis. Microscopic examination confirmed severe ulceration and basal cell vacuolation with basilar vesicle formation in the remaining intact epidermis. Immunohistochemistry for cytokeratin 5 demonstrated lack of epidermal immunoreactivity in homozygotes. DNA sequencing identified a 34-base pair insertion variant in exon 5 of the KRT5 gene. To our knowledge, this is the first report of epidermolysis bullosa in rhesus macaques.
Asunto(s)
Epidermólisis Ampollosa Simple/veterinaria , Variación Genética , Queratina-5/genética , Enfermedades de los Monos/diagnóstico , Animales , Modelos Animales de Enfermedad , Epidermólisis Ampollosa Simple/diagnóstico , Epidermólisis Ampollosa Simple/genética , Epidermólisis Ampollosa Simple/patología , Exones/genética , Femenino , Homocigoto , Humanos , Inmunohistoquímica/veterinaria , Queratinocitos/patología , Macaca mulatta , Masculino , Enfermedades de los Monos/genética , Enfermedades de los Monos/patología , Mutagénesis Insercional , Fenotipo , Piel/patología , Mortinato/veterinariaRESUMEN
Allogeneic hematopoietic stem cell transplantation (HSCT) and xenotransplantation are accompanied by viral reactivations and virus-associated complications resulting from immune deficiency. Here, in a Mauritian cynomolgus macaque model of fully MHC-matched allogeneic HSCT, we report reactivations of cynomolgus polyomavirus, lymphocryptovirus, and cytomegalovirus, macaque viruses analogous to HSCT-associated human counterparts BK virus, Epstein-Barr virus, and human cytomegalovirus. Viral replication in recipient macaques resulted in characteristic disease manifestations observed in HSCT patients, such as polyomavirus-associated hemorrhagic cystitis and tubulointerstitial nephritis or lymphocryptovirus-associated post-transplant lymphoproliferative disorder. However, in most cases, the reconstituted immune system, alone or in combination with short-term pharmacological intervention, exerted control over viral replication, suggesting engraftment of functional donor-derived immunity. Indeed, the donor-derived reconstituted immune systems of two long-term engrafted HSCT recipient macaques responded to live attenuated yellow fever 17D vaccine (YFV 17D) indistinguishably from untransplanted controls, mounting 17D-targeted neutralizing antibody responses and clearing YFV 17D within 14 days. Together, these data demonstrate that this macaque model of allogeneic HSCT recapitulates clinical situations of opportunistic viral infections in transplant patients and provides a pre-clinical model to test novel prophylactic and therapeutic modalities.
Asunto(s)
Modelos Animales de Enfermedad , Trasplante de Células Madre Hematopoyéticas , Infecciones Oportunistas , Virosis , Aloinjertos , Animales , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Macaca fascicularis , Infecciones Oportunistas/virologíaRESUMEN
Zika virus infection during pregnancy is associated with miscarriage and with a broad spectrum of fetal and neonatal developmental abnormalities collectively known as congenital Zika syndrome (CZS). Symptomology of CZS includes malformations of the brain and skull, neurodevelopmental delay, seizures, joint contractures, hearing loss and visual impairment. Previous studies of Zika virus in pregnant rhesus macaques (Macaca mulatta) have described injury to the developing fetus and pregnancy loss, but neonatal outcomes following fetal Zika virus exposure have yet to be characterized in nonhuman primates. Herein we describe the presentation of rhesus macaque neonates with a spectrum of clinical outcomes, including one infant with CZS-like symptoms including cardiomyopathy, motor delay and seizure activity following maternal infection with Zika virus during the first trimester of pregnancy. Further characterization of this neonatal nonhuman primate model of gestational Zika virus infection will provide opportunities to evaluate the efficacy of pre- and postnatal therapeutics for gestational Zika virus infection and CZS.
Asunto(s)
Modelos Animales de Enfermedad , Infección por el Virus Zika/veterinaria , Virus Zika/patogenicidad , Animales , Cardiomiopatías/virología , Femenino , Feto/virología , Macaca mulatta , Microcefalia/virología , Embarazo , Complicaciones Infecciosas del Embarazo/veterinaria , Complicaciones Infecciosas del Embarazo/virología , Primer Trimestre del Embarazo , Convulsiones/virología , Infección por el Virus Zika/virologíaRESUMEN
The development of therapies for retinal disorders is hampered by a lack of appropriate animal models. Higher nonhuman primates are the only animals with retinal structure similar to humans, including the presence of a macula and fovea. However, few nonhuman primate models of genetic retinal disease are known. We identified a lineage of rhesus macaques with a frameshift mutation in exon 3 of the BBS7 gene c.160delG (p.Ala54fs) that is predicted to produce a non-functional protein. In humans, mutations in this and other BBS genes cause Bardet-Biedl syndrome, a ciliopathy and a syndromic form of retinitis pigmentosa generally occurring in conjunction with kidney dysfunction, polydactyly, obesity, and/or hypogonadism. Three full- or half-sibling monkeys homozygous for the BBS7 c.160delG variant, at ages 3.5, 4 and 6 years old, displayed a combination of severe photoreceptor degeneration and progressive kidney disease. In vivo retinal imaging revealed features of severe macular degeneration, including absence of photoreceptor layers, degeneration of the retinal pigment epithelium, and retinal vasculature atrophy. Electroretinography in the 3.5-year-old case demonstrated loss of scotopic and photopic a-waves and markedly reduced and delayed b-waves. Histological assessments in the 4- and 6-year-old cases confirmed profound loss of photoreceptors and inner retinal neurons across the posterior retina, with dramatic thinning and disorganization of all cell layers, abundant microglia, absent or displaced RPE cells, and significant gliosis in the subretinal space. Retinal structure, including presence of photoreceptors, was preserved only in the far periphery. Ultrasound imaging of the kidneys revealed deranged architecture, and renal histopathology identified distorted contours with depressed, fibrotic foci and firmly adhered renal capsules; renal failure occurred in the 6-year-old case. Magnetic resonance imaging obtained in one case revealed abnormally low total brain volume and unilateral ventricular enlargement. The one male had abnormally small testes at 4 years of age, but polydactyly and obesity were not observed. Thus, monkeys homozygous for the BBS7 c.160delG variant closely mirrored several key features of the human BBS syndrome. This finding represents the first identification of a naturally-occurring nonhuman primate model of BBS, and more broadly the first such model of retinitis pigmentosa and a ciliopathy with an associated genetic mutation. This important new preclinical model will provide the basis for better understanding of disease progression and for the testing of new therapeutic options, including gene and cell-based therapies, not only for BBS but also for multiple forms of photoreceptor degeneration.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Síndrome de Bardet-Biedl/diagnóstico , Ceguera/etiología , Proteínas del Citoesqueleto/genética , ADN/genética , Mutación del Sistema de Lectura , Retina/patología , Retinitis Pigmentosa/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Síndrome de Bardet-Biedl/complicaciones , Síndrome de Bardet-Biedl/genética , Encéfalo/patología , Proteínas del Citoesqueleto/metabolismo , Análisis Mutacional de ADN , Modelos Animales de Enfermedad , Electrorretinografía , Femenino , Angiografía con Fluoresceína/métodos , Fondo de Ojo , Inmunohistoquímica , Macaca mulatta , Imagen por Resonancia Magnética , Masculino , Tomografía de Coherencia Óptica/métodosRESUMEN
Zika virus (ZIKV) infection during pregnancy causes congenital abnormalities, including microcephaly. However, rates vary widely, and the contributing risk factors remain unclear. We examined the serum antibody response to ZIKV and other flaviviruses in Brazilian women giving birth during the 2015-2016 outbreak. Infected pregnancies with intermediate or higher ZIKV antibody enhancement titers were at increased risk to give birth to microcephalic infants compared with those with lower titers (P < 0.0001). Similarly, analysis of ZIKV-infected pregnant macaques revealed that fetal brain damage was more frequent in mothers with higher enhancement titers. Thus, features of the maternal antibodies are associated with and may contribute to the genesis of ZIKV-associated microcephaly.
Asunto(s)
Anticuerpos Antivirales/inmunología , Intercambio Materno-Fetal/inmunología , Microcefalia/inmunología , Complicaciones Infecciosas del Embarazo/inmunología , Infección por el Virus Zika/inmunología , Virus Zika/inmunología , Animales , Encéfalo/embriología , Encéfalo/inmunología , Encéfalo/patología , Femenino , Feto/embriología , Feto/inmunología , Feto/patología , Humanos , Células K562 , Macaca mulatta , Macaca nemestrina , Microcefalia/patología , Embarazo , Complicaciones Infecciosas del Embarazo/patología , Infección por el Virus Zika/patologíaRESUMEN
Zika virus (ZIKV) infection is associated with congenital defects and pregnancy loss. Here, we found that 26% of nonhuman primates infected with Asian/American ZIKV in early gestation experienced fetal demise later in pregnancy despite showing few clinical signs of infection. Pregnancy loss due to asymptomatic ZIKV infection may therefore be a common but under-recognized adverse outcome related to maternal ZIKV infection.
Asunto(s)
Aborto Espontáneo/virología , Mortinato/veterinaria , Infección por el Virus Zika/veterinaria , Virus Zika/fisiología , Animales , Femenino , Estimación de Kaplan-Meier , Masculino , Embarazo , PrimatesRESUMEN
We have identified a natural Japanese macaque model of the childhood neurodegenerative disorder neuronal ceroid lipofuscinosis, commonly known as Batten Disease, caused by a homozygous frameshift mutation in the CLN7 gene (CLN7-/-). Affected macaques display progressive neurological deficits including visual impairment, tremor, incoordination, ataxia and impaired balance. Imaging, functional and pathological studies revealed that CLN7-/- macaques have reduced retinal thickness and retinal function early in disease, followed by profound cerebral and cerebellar atrophy that progresses over a five to six-year disease course. Histological analyses showed an accumulation of cerebral, cerebellar and cardiac storage material as well as degeneration of neurons, white matter fragmentation and reactive gliosis throughout the brain of affected animals. This novel CLN7-/- macaque model recapitulates key behavioral and neuropathological features of human Batten Disease and provides novel insights into the pathophysiology linked to CLN7 mutations. These animals will be invaluable for evaluating promising therapeutic strategies for this devastating disease.
Asunto(s)
Modelos Animales de Enfermedad , Proteínas de Transporte de Membrana/genética , Lipofuscinosis Ceroideas Neuronales/diagnóstico por imagen , Lipofuscinosis Ceroideas Neuronales/genética , Animales , Femenino , Técnicas de Inactivación de Genes/métodos , Locomoción/fisiología , Macaca , Masculino , Mutación Missense/genética , Lipofuscinosis Ceroideas Neuronales/fisiopatología , Equilibrio Postural/fisiología , Primates , Trastornos de la Visión/diagnóstico por imagen , Trastornos de la Visión/genética , Trastornos de la Visión/fisiopatologíaRESUMEN
Zika virus (ZIKV) infection during pregnancy leads to an increased risk of fetal growth restriction and fetal central nervous system malformations, which are outcomes broadly referred to as the Congenital Zika Syndrome (CZS). Here we infect pregnant rhesus macaques and investigate the impact of persistent ZIKV infection on uteroplacental pathology, blood flow, and fetal growth and development. Despite seemingly normal fetal growth and persistent fetal-placenta-maternal infection, advanced non-invasive in vivo imaging studies reveal dramatic effects on placental oxygen reserve accompanied by significantly decreased oxygen permeability of the placental villi. The observation of abnormal oxygen transport within the placenta appears to be a consequence of uterine vasculitis and placental villous damage in ZIKV cases. In addition, we demonstrate a robust maternal-placental-fetal inflammatory response following ZIKV infection. This animal model reveals a potential relationship between ZIKV infection and uteroplacental pathology that appears to affect oxygen delivery to the fetus during development.
Asunto(s)
Placenta/metabolismo , Circulación Placentaria , Complicaciones Infecciosas del Embarazo/inmunología , Infección por el Virus Zika/inmunología , Inmunidad Adaptativa , Animales , Encéfalo/embriología , Encéfalo/patología , Citocinas/sangre , Modelos Animales de Enfermedad , Femenino , Desarrollo Fetal , Feto/patología , Inmunidad Innata , Macaca mulatta , Imagen por Resonancia Magnética , Oxígeno/metabolismo , Permeabilidad , Placenta/inmunología , Placenta/patología , Placenta/virología , Embarazo , Complicaciones Infecciosas del Embarazo/metabolismo , Complicaciones Infecciosas del Embarazo/patología , Complicaciones Infecciosas del Embarazo/fisiopatología , Carga Viral , Infección por el Virus Zika/metabolismo , Infección por el Virus Zika/patología , Infección por el Virus Zika/fisiopatologíaRESUMEN
Allogeneic hematopoietic stem cell transplantation (HSCT) is a critically important therapy for hematological malignancies, inborn errors of metabolism, and immunodeficiency disorders, yet complications such as graft-vs.-host disease (GvHD) limit survival. Development of anti-GvHD therapies that do not adversely affect susceptibility to infection or graft-vs.-tumor immunity are hampered by the lack of a physiologically relevant, preclinical model of allogeneic HSCT. Here we show a spectrum of diverse clinical HSCT outcomes including primary and secondary graft failure, lethal GvHD, and stable, disease-free full donor engraftment using reduced intensity conditioning and mobilized peripheral blood HSCT in unrelated, fully MHC-matched Mauritian-origin cynomolgus macaques. Anti-GvHD prophylaxis of tacrolimus, post-transplant cyclophosphamide, and CD28 blockade induces multi-lineage, full donor chimerism and recipient-specific tolerance while maintaining pathogen-specific immunity. These results establish a new preclinical allogeneic HSCT model for evaluation of GvHD prophylaxis and next-generation HSCT-mediated therapies for solid organ tolerance, cure of non-malignant hematological disease, and HIV reservoir clearance.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Macaca fascicularis/inmunología , Complejo Mayor de Histocompatibilidad , Animales , Femenino , Enfermedad Injerto contra Huésped/prevención & control , Prueba de Histocompatibilidad , Humanos , Macaca fascicularis/genética , Masculino , Modelos Animales , Especificidad de la Especie , Quimera por Trasplante/genética , Quimera por Trasplante/inmunología , Tolerancia al Trasplante/genética , Tolerancia al Trasplante/inmunología , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Chikungunya virus (CHIKV) is a mosquito-borne virus that causes a febrile syndrome in humans associated with acute and chronic debilitating joint and muscle pain. Currently no licensed vaccines or therapeutics are available to prevent or treat CHIKV infections. We recently isolated a panel of potently neutralizing human monoclonal antibodies (mAbs), one (4N12) of which exhibited prophylactic and post-exposure therapeutic activity against CHIKV in immunocompromised mice. Here, we describe the development of an engineered CHIKV mAb, designated SVIR001, that has similar antigen binding and neutralization profiles to its parent, 4N12. Because therapeutic administration of SVIR001 in immunocompetent mice significantly reduced viral load in joint tissues, we evaluated its efficacy in a rhesus macaque model of CHIKV infection. Rhesus macaques that were treated after infection with SVIR001 showed rapid elimination of viremia and less severe joint infiltration and disease compared to animals treated with SVIR002, an isotype control mAb. SVIR001 reduced viral burden at the site of infection and at distant sites and also diminished the numbers of activated innate immune cells and levels of pro-inflammatory cytokines and chemokines. SVIR001 therapy; however, did not substantively reduce the induction of CHIKV-specific B or T cell responses. Collectively, these results show promising therapeutic activity of a human anti-CHIKV mAb in rhesus macaques and provide proof-of-principle for its possible use in humans to treat active CHIKV infections.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Antivirales/administración & dosificación , Fiebre Chikungunya/terapia , Factores Inmunológicos/administración & dosificación , Animales , Linfocitos B/inmunología , Fiebre Chikungunya/patología , Virus Chikungunya/inmunología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Macaca mulatta , Linfocitos T/inmunología , Resultado del TratamientoRESUMEN
[This corrects the article DOI: 10.1371/journal.ppat.1006219.].
RESUMEN
Zika virus (ZIKV), an emerging flavivirus, has recently spread explosively through the Western hemisphere. In addition to symptoms including fever, rash, arthralgia, and conjunctivitis, ZIKV infection of pregnant women can cause microcephaly and other developmental abnormalities in the fetus. We report herein the results of ZIKV infection of adult rhesus macaques. Following subcutaneous infection, animals developed transient plasma viremia and viruria from 1-7 days post infection (dpi) that was accompanied by the development of a rash, fever and conjunctivitis. Animals produced a robust adaptive immune response to ZIKV, although systemic cytokine response was minimal. At 7 dpi, virus was detected in peripheral nervous tissue, multiple lymphoid tissues, joints, and the uterus of the necropsied animals. Notably, viral RNA persisted in neuronal, lymphoid and joint/muscle tissues and the male and female reproductive tissues through 28 to 35 dpi. The tropism and persistence of ZIKV in the peripheral nerves and reproductive tract may provide a mechanism of subsequent neuropathogenesis and sexual transmission.
Asunto(s)
Infección por el Virus Zika/patología , Infección por el Virus Zika/virología , Animales , Separación Celular , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Hibridación in Situ , Macaca mulatta , Masculino , Pruebas de Neutralización , Reacción en Cadena de la Polimerasa , Viremia/virología , Virus ZikaRESUMEN
Bacterial infection of the laryngeal air sacs (air sacculitis) is infrequently reported in nonhuman primates, where it leads to chronic respiratory disease. It is particularly uncommon in macaques; however, we report here suppurative air sacculitis with extension to adjacent cervical tissues in three rhesus macaques and one Japanese macaque. Staphylococcus aureus, Streptococcus sp., and an anaerobic bacterium were isolated.