RESUMEN
This study's objective was to assess the effects of PD-0360324, a fully human immunoglobulin G2 monoclonal antibody against macrophage colony-stimulating factor in cutaneous lupus erythematosus (CLE). Patients with active subacute CLE or discoid lupus erythematosus were randomized to receive 100 or 150 mg PD-0360324 or placebo via intravenous infusion every 2 weeks for 3 months. Blood and urine samples were obtained pre- and post-treatment to analyse pharmacokinetics and pharmacodynamic changes in CD14(+) CD16(+) monocytes, urinary N-terminal telopeptide (uNTX), alanine/aspartate aminotransferases (ALT/AST) and creatine kinase (CK); tissue biopsy samples were taken to evaluate macrophage populations and T cells using immunohistochemistry. Clinical efficacy assessments included the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). Among 28 randomized/analysed patients, peak/trough plasma concentrations increased in a greater-than-dose-proportional manner with dose increases from 100 to 150 mg. Statistically significant differences were observed between active treatment and placebo groups in changes from baseline in CD14(+) CD16(+) cells, uNTX, ALT, AST and CK levels at most time-points. The numbers, density and activation states of tissue macrophages and T cells did not change from baseline to treatment end. No between-group differences were seen in CLASI. Patients receiving PD-0360324 reported significantly more adverse events than those receiving placebo, but no serious adverse events. In patients with CLE, 100 and 150 mg PD-0360324 every 2 weeks for 3 months suppressed a subset of circulating monocytes and altered activity of some tissue macrophages without affecting cell populations in CLE skin lesions or improving clinical end-points.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Lupus Eritematoso Cutáneo/tratamiento farmacológico , Lupus Eritematoso Cutáneo/inmunología , Factor Estimulante de Colonias de Macrófagos/inmunología , Macrófagos/inmunología , Monocitos/inmunología , Administración Intravenosa , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/inmunología , Aspartato Aminotransferasas/orina , Colágeno/orina , Creatina Quinasa/orina , Método Doble Ciego , Femenino , Histiocitos/efectos de los fármacos , Histiocitos/patología , Humanos , Inmunohistoquímica , Inmunoterapia , Receptores de Lipopolisacáridos/inmunología , Masculino , Persona de Mediana Edad , Receptores de IgG/inmunología , Índice de Severidad de la Enfermedad , Piel/efectos de los fármacos , Piel/patología , Adulto JovenRESUMEN
BACKGROUND: Simian immunodeficiency virus (SIV) infection and persistent CD8(+) lymphocyte depletion rapidly leads to encephalitis and neuronal injury. The objective of this study is to confirm that CD8 depletion alone does not induce brain lesions in the absence of SIV infection. METHODS: Four rhesus macaques were monitored by proton magnetic resonance spectroscopy ((1) H-MRS) before and biweekly after anti-CD8 antibody treatment for 8 weeks and compared with four SIV-infected animals. Post-mortem immunohistochemistry was performed on these eight animals and compared with six uninfected, non-CD8-depleted controls. RESULTS: CD8-depleted animals showed stable metabolite levels and revealed no neuronal injury, astrogliosis or microglial activation in contrast to SIV-infected animals. CONCLUSIONS: Alterations observed in MRS and lesions in this accelerated model of neuroAIDS result from unrestricted viral expansion in the setting of immunodeficiency rather than from CD8(+) lymphocyte depletion alone.
Asunto(s)
Encéfalo/patología , Linfocitos T CD8-positivos/patología , Depleción Linfocítica/veterinaria , Macaca mulatta , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Animales , Anticuerpos Monoclonales/metabolismo , Astrocitos/metabolismo , Astrocitos/patología , Astrocitos/virología , Encéfalo/metabolismo , Encéfalo/virología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/virología , Modelos Animales de Enfermedad , Encefalitis Viral/inmunología , Encefalitis Viral/metabolismo , Encefalitis Viral/patología , Encefalitis Viral/veterinaria , Citometría de Flujo/veterinaria , Proteína Ácida Fibrilar de la Glía/metabolismo , Inmunohistoquímica/veterinaria , Espectroscopía de Resonancia Magnética , Proteínas de Microfilamentos/metabolismo , Microglía/metabolismo , Microglía/patología , Microglía/virología , Proteínas Asociadas a Microtúbulos/metabolismo , Enfermedades de los Monos/inmunología , Enfermedades de los Monos/patología , Enfermedades de los Monos/virología , Neuronas/metabolismo , Neuronas/patología , Neuronas/virología , Protones , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/fisiología , Sinaptofisina/metabolismoRESUMEN
Epstein-Barr virus (EBV) is a worldwide endemic gamma herpesvirus of the genus Lymphocryptovirus (LCV) that infects more than 90% of the world's population. EBV has been associated with a variety of malignancies, but it has a demonstrated role in lymphomas, especially in immunosuppressed individuals. Lymphomas of the nasal cavity, paranasal sinuses, and nasopharynx are uncommon and constitute less than 5% of all extranodal lymphomas. Sinonasal non-Hodgkin's lymphomas have been reported in patients infected with human immunodeficiency virus (HIV) at an increased frequency. Rhesus LCV (rhLCV), the rhesus viral homolog of EBV, has been cloned and is associated with B-cell lymphomas in immunosuppressed rhesus macaques. We report two cases of B-cell lymphoma within the nasal cavity from 2 simian immunodeficiency virus-infected rhesus macaques with acquired immunodeficiency syndrome. The B-cell phenotype and rhLCV association were demonstrated by immunohistochemistry and confocal microscopy. The majority of the nuclei of the neoplastic B lymphocytes were EBNA-2 positive. RhLCV type 1 sequences were verified from the neoplasms by polymerase chain reaction. Nasal lymphoma is an unusual presentation of rhLCV-associated B-cell lymphoma in immunosuppressed rhesus macaques. These tumors demonstrate comparable viral pathogenesis with EBV-induced nasal lymphomas in HIV-positive people.
Asunto(s)
Lymphocryptovirus/aislamiento & purificación , Linfoma de Células B/veterinaria , Enfermedades de los Monos/patología , Neoplasias Nasales/veterinaria , Virus de la Inmunodeficiencia de los Simios , Animales , Lymphocryptovirus/clasificación , Linfoma de Células B/patología , Linfoma de Células B/virología , Macaca mulatta , Masculino , Enfermedades de los Monos/virología , Neoplasias Nasales/patologíaRESUMEN
A 20-year old male cotton-top tamarin (Saguinus oedipus) was presented with unilateral enlargement of an intrascrotal testicle. Fine-needle aspiration cytology demonstrated a neoplastic population with Call-Exner-like bodies and features of malignancy. The animal was castrated, and histologic examination revealed a biphasic sex cord-stromal tumor, with one region resembling Sertoli-cell tumor and one region resembling granulosa-cell tumor, with extensive microfollicular pattern and many Call-Exner bodies. Eight months after castration, the animal was euthanized on discovery of a caudal abdominal mass that displaced organs, was highly infiltrative, and extended into the paravertebral musculature with lysis of vertebral bone. Metastases to lymph node and lung were also present. Histologic examination of the abdominal tumor showed multifocal formation of Call-Exner bodies in an otherwise highly dedifferentiated population. Positive immunolabeling for alpha inhibin confirmed the sex cord-stromal origin of the abdominal and paravertebral tumor masses. This case has similarities to malignant testicular granulosa-cell tumor of humans.
Asunto(s)
Enfermedades de los Monos/patología , Tumores de los Cordones Sexuales y Estroma de las Gónadas/veterinaria , Neoplasias Testiculares/veterinaria , Neoplasias Abdominales/secundario , Animales , Neoplasias Pulmonares/secundario , Masculino , Saguinus , Tumores de los Cordones Sexuales y Estroma de las Gónadas/patología , Neoplasias Testiculares/patologíaRESUMEN
In a retrospective study, 51 cases of gastritis (14%) were identified from among 341 necropsies performed on simian immunodeficiency virus (SIV)-infected rhesus macaques (Macaca mulatta) at the New England Primate Research Center from 1993 to 2001. Protozoa were seen in the stomach of 13 monkeys (25%) with gastritis. Two histopathologic manifestations of gastritis were observed: seven cases of lymphoplasmacytic gastritis with trichomonad trophozoites within lumens of gastric glands and four cases of necrosuppurative gastritis containing intralesional periodic acid-Schiff-positive protozoa; two cases of gastritis had morphologic features of both types of gastritis. In instances of necrosuppurative and combined lymphoplasmacytic and necrosuppurative gastritis, protozoa were 4-35 microm in diameter and round to tear-shaped. Because of the unusual morphology of the protozoa in these latter cases, transmission electron microscopy and polymerase chain reaction (PCR) were used to further identify these organisms. The protozoa were definitively identified as Tritrichomonas in all cases on the basis of ultrastructural characteristics (flagella and undulating membranes) and amplification of a 347-bp product of the 5.8S ribosomal RNA gene of Tritrichomonas foetus, Tritrichomonas suis and Tritrichomonas mobilensis by PCR using DNA extracted from stomach tissue. On the basis of these observations, we conclude that Tritrichomonas can be a significant cofactor in the development of necrosuppurative gastritis in SIV-infected rhesus macaques.
Asunto(s)
Gastritis/veterinaria , Macaca mulatta , Enfermedades de los Monos/parasitología , Enfermedades de los Monos/virología , Infecciones Protozoarias en Animales , Infecciones por Protozoos/virología , Síndrome de Inmunodeficiencia Adquirida del Simio/parasitología , Virus de la Inmunodeficiencia de los Simios/crecimiento & desarrollo , Tritrichomonas/crecimiento & desarrollo , Animales , ADN Protozoario/química , ADN Protozoario/genética , Femenino , Gastritis/patología , Gastritis/virología , Inmunohistoquímica/veterinaria , Hibridación in Situ/veterinaria , Masculino , Microscopía Electrónica de Transmisión/veterinaria , Enfermedades de los Monos/patología , Reacción en Cadena de la Polimerasa/veterinaria , Infecciones por Protozoos/parasitología , Infecciones por Protozoos/patología , ARN Protozoario/química , ARN Protozoario/genética , ARN Ribosómico 5.8S/química , ARN Ribosómico 5.8S/genética , Estudios Retrospectivos , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Tritrichomonas/genética , Tritrichomonas/ultraestructuraRESUMEN
Heterologous prime/boost regimens have the potential for raising high levels of immune responses. Here we report that DNA priming followed by a recombinant modified vaccinia Ankara (rMVA) booster controlled a highly pathogenic immunodeficiency virus challenge in a rhesus macaque model. Both the DNA and rMVA components of the vaccine expressed multiple immunodeficiency virus proteins. Two DNA inoculations at 0 and 8 weeks and a single rMVA booster at 24 weeks effectively controlled an intrarectal challenge administered 7 months after the booster. These findings provide hope that a relatively simple multiprotein DNA/MVA vaccine can help to control the acquired immune deficiency syndrome epidemic.
Asunto(s)
Vacunas contra el SIDA/inmunología , Síndrome de Inmunodeficiencia Adquirida/prevención & control , Vacunas de ADN/inmunología , Vacunas contra el SIDA/administración & dosificación , Síndrome de Inmunodeficiencia Adquirida/inmunología , Síndrome de Inmunodeficiencia Adquirida/virología , Animales , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Centro Germinal/inmunología , Anticuerpos Anti-VIH/sangre , Anticuerpos Anti-VIH/inmunología , VIH-1/genética , VIH-1/inmunología , VIH-1/fisiología , Inmunidad Mucosa , Inmunización Secundaria , Memoria Inmunológica , Interferón gamma/biosíntesis , Ganglios Linfáticos/inmunología , Macaca mulatta , Vacunas contra el SIDAS/administración & dosificación , Vacunas contra el SIDAS/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/genética , Virus de la Inmunodeficiencia de los Simios/inmunología , Virus de la Inmunodeficiencia de los Simios/fisiología , Linfocitos T/inmunología , Vacunas de ADN/administración & dosificación , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/inmunología , Virus Vaccinia/inmunología , Carga ViralRESUMEN
To investigate the pathogenicity of a virus originating in a chimpanzee with AIDS (C499), two chimpanzees were inoculated with a plasma-derived isolate termed human immunodeficiency virus type 1(NC) (HIV-1(NC)). A previously uninfected chimpanzee, C534, experienced rapid peripheral CD4(+) T-cell loss to fewer than 26 cells/microl by 14 weeks after infection. CD4(+) T-cell depletion was associated with high plasma HIV-1 loads but a low virus burden in the peripheral lymph node. The second chimpanzee, C459, infected 13 years previously with HIV-1(LAV), experienced a more protracted course of peripheral CD4(+) T-cell loss after HIV-1(NC) inoculation, resulting in fewer than 200 cells/microl by 96 weeks postinoculation. The quantities of viral RNA in the plasma and peripheral lymph node from C459 were below the lower limits of detection prior to inoculation with HIV-1(NC) but were significantly and persistently increased after superinfection, with HIV-1(NC) representing the predominant viral genotype. These results show that viruses derived from C499 are more pathogenic for chimpanzees than any other HIV-1 isolates described to date.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/inmunología , Linfocitos T CD4-Positivos/fisiología , VIH-1/patogenicidad , Síndrome de Inmunodeficiencia Adquirida/virología , Animales , Secuencia de Bases , VIH-1/aislamiento & purificación , Ganglios Linfáticos/virología , Datos de Secuencia Molecular , Pan troglodytes , ARN Viral/sangreRESUMEN
Chimpanzees are susceptible to infection with human immunodeficiency virus (HIV)-1; however, infected animals usually maintain normal numbers of CD4(+) T lymphocytes and do not develop immunodeficiency. We have examined 10 chronically infected HIV-1-positive chimpanzees for evidence of progressive infection. In addition to 1 animal that developed AIDS, 3 chimpanzees exhibit evidence of progressive HIV infection. All progressors have low CD4(+) T cell counts (<200 cells/microL), severe CD4:CD8 inversion, and marked reduction in interleukin-2 receptor expression by CD4(+) T cells. In comparison with HIV-positive nonprogressor chimpanzees, progressors have higher plasma and lymphoid virus loads, greater CD38 expression in CD8(+)/HLA-DR(+) T cells, and greater serum concentrations of soluble tumor necrosis factor type II receptors and beta2-microglobulin, all markers of HIV progression in humans. These observations show that progressive HIV-1 infection can occur in chimpanzees and suggest that the pathogenesis of progressive infection in this species resembles that in humans.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/fisiopatología , Antígenos CD , Infecciones por VIH/fisiopatología , Seropositividad para VIH/fisiopatología , ADP-Ribosil Ciclasa , ADP-Ribosil Ciclasa 1 , Síndrome de Inmunodeficiencia Adquirida/inmunología , Animales , Antígenos de Diferenciación/sangre , Recuento de Linfocito CD4 , Relación CD4-CD8 , Progresión de la Enfermedad , Femenino , Infecciones por VIH/inmunología , Infecciones por VIH/patología , Seropositividad para VIH/inmunología , Seropositividad para VIH/patología , Antígenos HLA-DR/sangre , Humanos , Integrina beta1/sangre , Ganglios Linfáticos/patología , Ganglios Linfáticos/virología , Subgrupos Linfocitarios/inmunología , Masculino , Glicoproteínas de Membrana , NAD+ Nucleosidasa/sangre , Pan troglodytes , Receptores de Interleucina-2/sangre , Linfocitos T/inmunología , Factores de TiempoRESUMEN
Simian immunodeficiency virus (SIV) variant SIVsmmPBj14 is unique in producing an acutely lethal enteropathic syndrome in pigtail macaques. To determine whether the nature of the PBj14 disease would be attenuated by decreasing virus input and to relate tissue virus burden to the severity of disease, we infected pigtail macaques with serial 10-fold doses of SIVsmmPBj14 clone bcl.3 spanning 10(-2) through 10(4)TCID50. The results revealed a strikingly narrow difference between minimum infectious and fatal disease-inducing doses and a close association between enteric lymphoid tissue virus burden and disease. All animals infected with as much as 10(4) TCID50 through as little as 100 TCID50 of virus died of the lethal PBj14 syndrome between 7 and 13 days postinfection. Animals receiving 10(-1) TCID50 became infected (PCR+) but did not develop clinical disease. Animals receiving 10(-2) TCID50 did not become infected. The clinical syndrome was surprisingly similar in all affected macaques, although the time to disease onset and total survival time increased slightly as virus input decreased from 10(4) to 10 degrees TCID50. Highest terminal virus loads in plasma, gut-associated lymphoid tissue (GALT), and lymph nodes and greatest lesion severity were attained at intermediate levels of virus input (10(1) to 10(2) TCID50), probably owing to optimal time for virus amplification in target tissues. The present study reinforces others on the PBj14 system, suggesting that once a threshold level of virus replication is attained in intestinal lymphoid tissues, the cascade of events precipitating the lethal PBj14 syndrome is triggered irreversibly.
Asunto(s)
Macaca nemestrina/virología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Animales , Anticuerpos Antivirales/sangre , Especificidad de Anticuerpos , Ensayo de Inmunoadsorción Enzimática , Femenino , Inmunohistoquímica , Ganglios Linfáticos/virología , Especificidad de Órganos , Reacción en Cadena de la Polimerasa , Provirus/aislamiento & purificación , Proteínas de los Retroviridae/sangre , Síndrome de Inmunodeficiencia Adquirida del Simio/diagnóstico , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/aislamiento & purificación , Carga Viral , Proteínas Virales/aislamiento & purificaciónRESUMEN
To gain insight into the unique pathogenicity of simian immunodeficiency virus (SIV) variant PBj14, which produces an acutely lethal enteropathic syndrome in infected pigtail macaques, we investigated the cell and tissue tropisms of a highly pathogenic biologic clone (bcl.3) of SIVsmmPBj14. To compare the relative amount of viral antigen in lymphoid organs of infected macaques we used an objective semiquantitative immunohistochemistry (sQIHC) assay. We found that in all animals viral antigen load was greater in alimentary-associated lymphoid tissues (gut-associated lymphoid tissue [GALT], tonsil, mesenteric and retropharyngeal lymph nodes) than in non-alimentary-associated lymphoid tissues (spleen, thymus, inguinal and axillary lymph nodes). Moreover, in six of nine animals examined, virus load in GALT was greater than that in any other lymphoid tissue. To determine whether the acute pathogenicity and prolific replication of SIVsmmPBj14 might be explained by a broader in vivo cell tropism than is typical of SIVs, we used cell subset separation and nested PCR. We found that the primary target cells in mesenteric lymph node for SIVsmmPBj14 were CD4+ T lymphocytes. However, the virus also infected macrophages, as well as CD8+ T cells and B cells, albeit at low frequencies. These results suggest that alimentary lymphoid tissue localization rather than unusual cell phenotype tropism distinguishes the singular pathogenesis of SIVsmmPBj14.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Animales , Axila , Linfocitos B/virología , Femenino , Citometría de Flujo , Ingle , Inmunohistoquímica , Hibridación in Situ , Intestinos , Ganglios Linfáticos/virología , Macaca nemestrina , Macrófagos/virología , Masculino , Reacción en Cadena de la Polimerasa , Provirus/aislamiento & purificación , ARN Viral/análisis , Bazo/virología , Subgrupos de Linfocitos T/virología , Timo/virología , Factores de Tiempo , Tropismo , Carga Viral , Replicación ViralRESUMEN
Transfusion of blood from a simian immunodeficiency virus (SIV)- and simian T-cell lymphotropic virus-infected sooty mangabey (designated FGb) to rhesus and pig-tailed macaques resulted in the development of neurologic disease in addition to AIDS. To investigate the role of SIV in neurologic disease, virus was isolated from a lymph node of a pig-tailed macaque (designated PGm) and the cerebrospinal fluid of a rhesus macaque (designated ROn2) and passaged to additional macaques. SIV-related neuropathogenic effects were observed in 100% of the pig-tailed macaques inoculated with either virus. Lesions in these animals included extensive formation of SIV RNA-positive giant cells in the brain parenchyma and meninges. Based upon morphology, the majority of infected cells in both lymphoid and brain tissue appeared to be of macrophage lineage. The virus isolates replicated very well in pig-tailed and rhesus macaque peripheral blood mononuclear cells (PBMC) with rapid kinetics. Differential replicative abilities were observed in both PBMC and macrophage populations, with viruses growing to higher titers in pig-tailed macaque cells than in rhesus macaque cells. An infectious molecular clone of virus derived from the isolate from macaque PGm (PGm5.3) was generated and was shown to have in vitro replication characteristics similar to those of the uncloned virus stock. While molecular analyses of this virus revealed its similarity to SIV isolates from sooty mangabeys, significant amino acid differences in Env and Nef were observed. This virus should provide an excellent system for investigating the mechanism of lentivirus-induced neurologic disease.
Asunto(s)
Infecciones del Sistema Nervioso Central/etiología , Cercocebus atys/virología , Síndrome de Inmunodeficiencia Adquirida del Simio/etiología , Virus de la Inmunodeficiencia de los Simios/aislamiento & purificación , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Complejo SIDA Demencia/etiología , Secuencia de Aminoácidos , Animales , Transfusión Sanguínea , Infecciones del Sistema Nervioso Central/patología , Infecciones del Sistema Nervioso Central/virología , Infecciones por Deltaretrovirus/etiología , Modelos Animales de Enfermedad , Genes env , Genes nef , Humanos , Hibridación in Situ , Leucocitos Mononucleares/virología , Macaca mulatta , Macaca nemestrina , Macrófagos/patología , Macrófagos/virología , Datos de Secuencia Molecular , Homología de Secuencia de Aminoácido , Síndrome de Inmunodeficiencia Adquirida del Simio/transmisión , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/genética , Virus Linfotrópico T Tipo 1 de los Simios , Replicación ViralRESUMEN
The condition of a chimpanzee (C499) infected with three different isolates of human immunodeficiency virus type 1 (HIV-1) for over 10 years progressed to AIDS. Disease development in this animal was characterized by (i) a decline in CD4+ cells over the last 3 years; (ii) an increase in viral loads in plasma; (iii) the presence of a virus, termed HIV-1JC, which is cytopathic for chimpanzee peripheral blood mononuclear cells; and (iv) the presence of an opportunistic infection and blood dyscrasias. Genetic analysis of the V1-V2 region of the envelope gene of HIV-1JC showed that the virus present in C499 was significantly divergent from all inoculating viruses (> or = 16% divergent at the amino acid level) and was suggestive of a large quasispecies. Blood from C499 transfused into an uninfected chimpanzee (C455) induced a rapid and sustained CD4+-cell decline in the latter animal, concomitant with high plasma viral loads. These results show that HIV-1 can induce AIDS in chimpanzees and suggest that long-term passage of HIV-1 in chimpanzees can result in the development of a more pathogenic virus.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/veterinaria , VIH-1 , Pan troglodytes/virología , Síndrome de Inmunodeficiencia Adquirida/sangre , Síndrome de Inmunodeficiencia Adquirida/virología , Secuencia de Aminoácidos , Animales , Recuento de Linfocito CD4 , Datos de Secuencia MolecularRESUMEN
Infection of pigtail macaques with SIVsmmPBj14, biological clone 3 (SIV-PBj14-bc13), produces an acute and usually fatal shock-like syndrome 7 to 14 days after infection. We used this simian immunodeficiency virus (SIV) model as a rapid and rigorous challenge to evaluate the efficacy of two SIV Env vaccine strategies. Groups of four pigtail macaques were immunized four times over a 25-week span with either a recombinant Semliki Forest virus expressing the SIV-PBj14 Env gp160 (SFV-SIVgp160) or purified recombinant SIV-PBj14 gp120 (rgp120) in SBN-1 adjuvant. Antibody titers to SIV Env developed in all immunized animals (mean peak titers prior to challenge, 1:1,700 for SFV-SIV gp 160 and 1:10,500 for rgp120), but neither neutralizing antibodies nor SIV-specific T-cell proliferative responses were detectable in any of the vaccinees. All macaques were challenged with a 100% infectious, 75% fatal dose of SIV-PBj14-bc13 at week 26. Three of four control animals died of acute SIV-PBj14 syndrome on days 12 and 13. By contrast, all four SFV-SIVgp160-immunized animals and three of the four rgp120-immunized animals were protected from lethal disease. While all virus-challenged animals became infected, symptoms of the SIV-PBj14 syndrome were more severe in controls than in vaccinees. Mean virus titers in plasma at 13 days postchallenge were approximately 10-fold lower in vaccinated than control animals. However, there was no apparent correlation between survival and levels of peripheral blood mononuclear cell-associated culturable virus, provirus load, or any antiviral immunologic parameter examined. The results indicate that while immunization with SFV-SIVgp160 and rgp120 did not protect against virus infection, these Env vaccines did lower the virus load in plasma and protect against the lethal SIV-PBj14 challenge.
Asunto(s)
Productos del Gen env/inmunología , Proteína gp120 de Envoltorio del VIH/inmunología , Glicoproteínas de Membrana , Vacunas contra el SIDAS/inmunología , Virus de los Bosques Semliki/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/inmunología , Proteínas del Envoltorio Viral , Animales , Anticuerpos Antivirales/inmunología , Secuencia de Bases , Recuento de Linfocito CD4 , Línea Celular , Células Cultivadas , Cricetinae , ADN Viral , Femenino , Productos del Gen env/genética , Vectores Genéticos/genética , Proteína gp120 de Envoltorio del VIH/genética , Humanos , Inmunidad Celular , Macaca nemestrina , Ratones , Datos de Secuencia Molecular , Virus de los Bosques Semliki/genética , Síndrome de Inmunodeficiencia Adquirida del Simio/mortalidad , Virus de la Inmunodeficiencia de los Simios/química , Virus de la Inmunodeficiencia de los Simios/crecimiento & desarrollo , Vacunas Sintéticas/inmunologíaRESUMEN
A monoclonal gammopathy composed of immunoglobulin G, with concurrent light-chain proteinuria and generalized lymph node plasmacytosis, was associated with chronic pyoderma in a dog. A uniform population of plasma cells was observed cytologically and histologically in multiple lymph node specimens. A diagnosis of monoclonal gammopathy of unknown significance was eventually made by exclusion of other known causes of monoclonal gammopathy, resolution after antibiotic therapy, and no evidence of lymphoproliferative disease after 11 months of follow-up and subsequent necropsy. This report expands the diagnostic considerations for monoclonal gammopathies in the dog.
Asunto(s)
Enfermedades de los Perros , Paraproteinemias/veterinaria , Piodermia/veterinaria , Animales , Enfermedad Crónica , Enfermedades de los Perros/patología , Perros , Femenino , Paraproteinemias/complicaciones , Paraproteinemias/patología , Piodermia/complicaciones , Piodermia/patologíaRESUMEN
We compared the efficacy of immunization with either simian immunodeficiency virus (SIV) Env glycoprotein (Env), Env plus Gag proteins (Gag-Env), or whole inactivated virus (WIV), with or without recombinant live vaccinia vector (VV) priming, in protecting 23 rhesus macaques (six vaccine and two control groups) from challenge with SIVmac251 clone BK28. Vaccination elicited high titers of syncytium-inhibiting and anti-Env (gp120/gp160) antibodies in all vaccinated macaques and anti-Gag (p27) antibodies in groups immunized with WIV or Gag-Env. Only WIV-immunized macaques developed anticell (HuT78) antibodies. After homologous low-dose intravenous virus challenge, we used frequency of virus isolation, provirus burden, and change in antibody titers to define four levels of resistance to SIV infection as follows. (i) No infection ("sterilizing" immunity) was induced only in WIV-immunized animals. (ii) Abortive infection (strong immunity) was defined when virus or provirus were detected early in the postchallenge period but not thereafter and no evidence of virus or provirus was detected in terminal tissues. This response was observed in two animals (one VV-Env and one Gag-Env). (iii) Suppression of infection (incomplete or partial immunity) described a gradient of virus suppression manifested by termination of viremia, declining postchallenge antibody titers, and low levels (composite mean = 9.1 copies per 10(6) cells) of provirus detectable in peripheral blood mononuclear cells or lymphoid tissues at termination (40 weeks postchallenge). This response occurred in the majority (8 of 12) of subunit-vaccinated animals. (iv) Active infection (no immunity) was characterized by persistent virus isolation from blood mononuclear cells, increasing viral antibody titers postchallenge, and high levels (composite mean = 198 copies per 10(6) cells) of provirus in terminal tissues and blood. Active infection developed in all controls and two of three VV-Gag-Env-immunized animals. The results of this study restate the protective effect of inactivated whole virus vaccines produced in heterologous cells but more importantly demonstrate that a gradient of suppression of challenge virus growth, reflecting partial resistance to SIV infection, is induced by subunit vaccination. The latter finding may be pertinent to studies with human immunodeficiency virus vaccines, in which it is plausible that vaccination may elicit significant suppression of virus infection and pathogenicity rather than sterilizing immunity.
Asunto(s)
Inmunoterapia Activa , Glicoproteínas de Membrana , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Vacunación , Vacunas Sintéticas , Proteínas del Envoltorio Viral , Vacunas Virales , Animales , Anticuerpos Antivirales/sangre , Secuencia de Bases , Sangre/microbiología , Células Cultivadas , Productos del Gen gag/genética , Productos del Gen gag/inmunología , Proteína gp120 de Envoltorio del VIH/genética , Proteína gp120 de Envoltorio del VIH/inmunología , Humanos , Inmunización Secundaria , Activación de Linfocitos , Macaca mulatta , Datos de Secuencia Molecular , Pruebas de Neutralización , Provirus/aislamiento & purificación , Proteínas Recombinantes/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Virus de la Inmunodeficiencia de los Simios/crecimiento & desarrollo , Virus Vaccinia/genéticaRESUMEN
We have studied the early pathogenesis of infection by molecular clone 1.9 of SIVsmmPBj14 in pig-tailed and cynomolgus macaques. Like the uncloned PBj14 parent, SIVsmmPBj14-1.9 consistently induced an acute clinical syndrome characterized by behavioral depression, fever, profuse diarrhea, dehydration, lymphadenopathy, splenomegaly, and mucocutaneous exanthema that began at 7 days postinfection (DPI). The acute clinical disease coincided with a marked cell-associated and cell-free viremia, during which SIV p27 was demonstrated in 4 to 68% of circulating mononuclear leukocytes between 4 and 17 DPI. Also characteristic were monocytosis and reductions in CD4+ and CD8+ T lymphocytes, as well as CD20+ B lymphocytes. The most profound depletion occurred in the CD44hi subset of CD4+ T cells. Unlike animals infected previously with uncloned or biologically cloned PBj14, however, all SIVsmmPBj14-1.9-infected macaques survived the acute-phase disease to progress to a chronic, largely asymptomatic phase of infection. Recovery from the acute-phase disease correlated with down modulation of virus replication and the appearance of antibodies to SIV Env and Gag proteins. Similar to the PBj14 parent, PBj14-1.9 targeted to intestine, spleen, bone marrow, lymph node, and cerebellum. Saliva contained substantial quantities of infectious virus and no viral antibodies during the early phase of infection. By contrast, saliva from chronically infected animals usually contained antibodies but no virus. This study extends previous work demonstrating that the acute clinical syndrome produced by SIVsmmPBj14 in pig-tailed macaques represents a unique model of lentiviral pathogenesis.