RESUMEN
Zika virus (ZIKV) is an emerging mosquito-borne flavivirus with devastating outcomes seen recently in the Americas due to the association of maternal ZIKV infection with fetal microcephaly and other fetal malformations not previously associated with flavivirus infections. Here, we have developed the olive baboon (Papio anubis) as a nonhuman primate (NHP) translational model for the study of ZIKV pathogenesis and associated disease outcomes to contrast and compare with humans and other major NHPs, such as macaques. Following subcutaneous inoculation of adult male and nonpregnant female baboons, viremia was detected at 3 and 4 days postinfection (dpi) with the concordant presentation of a visible rash and conjunctivitis, similar to human ZIKV infection. Furthermore, virus was detected in the mucosa and cerebrospinal fluid. A robust ZIKV-specific IgM and IgG antibody response was also observed in all the animals. These data show striking similarity between humans and the olive baboon following infection with ZIKV, suggesting our model is a suitable translational NHP model to study ZIKV pathogenesis and potential therapeutics.IMPORTANCE ZIKV was first identified in 1947 in a sentinel rhesus monkey in Uganda and subsequently spread to Southeast Asia. Until 2007, only a small number of cases were reported, and ZIKV infection was relatively minor until the South Pacific and Brazilian outbreaks, where more severe outcomes were reported. Here, we present the baboon as a nonhuman primate model for contrast and comparison with other published animal models of ZIKV, such as the mouse and macaque species. Baboons breed year round and are not currently a primary nonhuman primate species used in biomedical research, making them more readily available for studies other than human immunodeficiency virus studies, which many macaque species are designated for. This, taken together with the similarities baboons have with humans, such as immunology, reproduction, genetics, and size, makes the baboon an attractive NHP model for ZIKV studies in comparison to other nonhuman primates.
Asunto(s)
Anticuerpos Antivirales/metabolismo , Modelos Animales de Enfermedad , Viremia/diagnóstico , Infección por el Virus Zika/diagnóstico , Virus Zika/patogenicidad , Animales , Brasil , Femenino , Humanos , Inmunoglobulina G/metabolismo , Inmunoglobulina M/metabolismo , Masculino , Membrana Mucosa/virología , Papio , Viremia/líquido cefalorraquídeo , Virus Zika/inmunología , Infección por el Virus Zika/líquido cefalorraquídeo , Infección por el Virus Zika/inmunologíaRESUMEN
We previously reported that galectin-9 (Gal-9), a soluble lectin with immunomodulatory properties, is elevated in plasma during HIV infection and induces HIV transcription. The link between Gal-9 and compromised neuronal function is becoming increasingly evident; however, the association with neuroHIV remains unknown. We measured Gal-9 levels by ELISA in cerebrospinal fluid (CSF) and plasma of 70 HIV-infected (HIV+) adults stratified by age (older > 40 years and younger < 40 years) either ART suppressed or with detectable CSF HIV RNA, including a subgroup with cognitive assessments, and 18 HIV uninfected (HIV-) controls. Gal-9 tissue expression was compared in necropsy brain specimens from HIV- and HIV+ donors using gene datasets and immunohistochemistry. Among older HIV+ adults, CSF Gal-9 was elevated in the ART suppressed and CSF viremic groups compared to controls, whereas in the younger group, Gal-9 levels were elevated only in the CSF viremic group (p < 0.05). CSF Gal-9 positively correlated with age in all groups (p < 0.05). CSF Gal-9 tracked with CSF HIV RNA irrespective of age (ß = 0.33; p < 0.05). Higher CSF Gal-9 in the older viremic HIV+ group correlated with worse neuropsychological test performance scores independently of age and CSF HIV RNA (p < 0.05). Furthermore, CSF Gal-9 directly correlated with myeloid activation (CSF-soluble CD163 and neopterin) in both HIV+ older groups (p < 0.05). Among HIV+ necropsy specimens, Gal-9 expression was increased in select brain regions compared to controls (p < 0.05). Gal-9 may serve as a novel neuroimmuno-modulatory protein that is involved in driving cognitive deficits in those aging with HIV and may be valuable in tracking cognitive abnormalities.
Asunto(s)
Antígenos CD/genética , Antígenos de Diferenciación Mielomonocítica/genética , Sistema Nervioso Central/virología , Galectinas/genética , Infecciones por VIH/virología , ARN Viral/genética , Receptores de Superficie Celular/genética , Viremia/virología , Adulto , Factores de Edad , Fármacos Anti-VIH/uso terapéutico , Antígenos CD/líquido cefalorraquídeo , Antígenos de Diferenciación Mielomonocítica/líquido cefalorraquídeo , Terapia Antirretroviral Altamente Activa , Biomarcadores/líquido cefalorraquídeo , Estudios de Casos y Controles , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/fisiopatología , Cognición/efectos de los fármacos , Cognición/fisiología , Femenino , Galectinas/líquido cefalorraquídeo , Infecciones por VIH/líquido cefalorraquídeo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , VIH-1/genética , VIH-1/patogenicidad , Humanos , Masculino , Persona de Mediana Edad , Neopterin/líquido cefalorraquídeo , Pruebas Neuropsicológicas , ARN Viral/líquido cefalorraquídeo , Viremia/líquido cefalorraquídeo , Viremia/tratamiento farmacológico , Viremia/inmunologíaRESUMEN
The majority of neurologically symptomatic cerebrospinal fluid HIV-1 escape cases are connected with resistance-associated mutations and potentially explained by low cerebrospinal fluid antiretroviral concentrations. However, there are still significant knowledge gaps regarding the physiopathology and long-term management of neurosymptomatic viral escape. We report a case of Parkinson-like syndrome following cerebrospinal fluid HIV-1 escape in a 40-year-old female patient with an history of persistent low-level plasma viremia under treatment. No resistance-associated mutations, high viral diversity (env deep sequencing), adequate pharmacokinetics, atypical CD3-CD14-CD4+CD5-CD2-/+CD7-/+ lymphocytes, low-level Epstein-Barr virus replication, and white matter autoimmune reactivity were observed in the cerebrospinal fluid. Antiretroviral regimen modification led to rapid clinical and radiological improvements. This case may increase the current uncertain knowledge on the origin of cerebrospinal fluid HIV-1 and illustrates the consequences of uncontrolled compartmental viral replication; it also highlights the relevance and persistence of immune activation and the possibility of various detrimental mechanisms underlying neurosymptomatic viral escape.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por Virus de Epstein-Barr/virología , Infecciones por VIH/virología , Enfermedad de Parkinson/virología , ARN Viral/genética , Parálisis Supranuclear Progresiva/virología , Viremia/virología , Adulto , Terapia Antirretroviral Altamente Activa , Sustitución de Medicamentos , Infecciones por Virus de Epstein-Barr/líquido cefalorraquídeo , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/tratamiento farmacológico , Femenino , Infecciones por VIH/líquido cefalorraquídeo , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , VIH-1/genética , VIH-1/crecimiento & desarrollo , VIH-1/patogenicidad , Herpesvirus Humano 4/efectos de los fármacos , Herpesvirus Humano 4/crecimiento & desarrollo , Herpesvirus Humano 4/patogenicidad , Humanos , Enfermedad de Parkinson/líquido cefalorraquídeo , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/tratamiento farmacológico , Parálisis Supranuclear Progresiva/líquido cefalorraquídeo , Parálisis Supranuclear Progresiva/complicaciones , Parálisis Supranuclear Progresiva/tratamiento farmacológico , Viremia/líquido cefalorraquídeo , Viremia/complicaciones , Viremia/tratamiento farmacológico , Replicación Viral/efectos de los fármacosRESUMEN
The central nervous system has been proposed as a sanctuary site where HIV can escape antiretroviral control and develop drug resistance. HIV-1 RNA can be at higher levels in CSF than plasma, termed CSF/plasma discordance. We aimed to examine whether discordance in CSF is associated with low level viraemia (LLV) in blood. In this MRC-funded multicentre study, we prospectively recruited patients with LLV, defined as one or more episode of unexplained plasma HIV-1 RNA within 12 months, and undertook CSF examination. Separately, we prospectively collected CSF from patients undergoing lumbar puncture for a clinical indication. Patients with durable suppression of viraemia and no evidence of CNS infection were identified as controls from this group. Factors associated with CSF/plasma HIV-1 discordance overall were examined. One hundred fifty-three patients were recruited across 13 sites; 40 with LLV and 113 undergoing clinical lumbar puncture. Seven of the 40 (18 %) patients with LLV had CSF/plasma discordance, which was significantly more than 0/43 (0 %) with durable suppression in blood from the clinical group (p = 0.005). Resistance associated mutations were shown in six CSF samples from discordant patients with LLV (one had insufficient sample for testing), which affected antiretroviral therapy at sampling in five. Overall discordance was present in 20/153 (13 %) and was associated with nadir CD4 but not antiretroviral concentrations in plasma or CSF. CSF/plasma discordance is observed in patients with LLV and is associated with antiretroviral resistance associated mutations in CSF. The implications for clinical practice require further investigation.
Asunto(s)
Infecciones por VIH/diagnóstico , ARN Viral/sangre , ARN Viral/líquido cefalorraquídeo , Viremia/diagnóstico , Adulto , Fármacos Anti-VIH/uso terapéutico , Recuento de Linfocito CD4 , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Sistema Nervioso Central/virología , Farmacorresistencia Viral/genética , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/líquido cefalorraquídeo , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , VIH-1/genética , VIH-1/crecimiento & desarrollo , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Estudios Prospectivos , ARN Viral/antagonistas & inhibidores , Viremia/sangre , Viremia/líquido cefalorraquídeo , Viremia/tratamiento farmacológicoRESUMEN
Hepatitis G virus or GB virus C (GBV-C) is a human virus of the Flaviviridae family that is structurally and epidemiologically closest to hepatitis C virus, but replicates primarily in lymphocytes. Co-infection with GBV-C has been reported to confer beneficial outcomes in some HIV-positive patients. Up to now, however, studies on GBV-C infection in the central nervous system (CNS) of HIV-infected patient have rarely been reported. Herein, we report on a 32-year-old HIV-1-infected patient with cerebral toxoplasmosis and fungal encephalitis. GBV-C viral loads were detected in CSF by quantitative real-time reverse transcription polymerase chain reaction (RT-PCR), and the results showed that GBV-C viral load was 6·5 log copies/ml. We amplified and sequenced the E2 and 5'-untranslated regions from the purified viral RNA from CSF by RT-PCR. Both sequences belong to genotype 3 and there were some minor nucleotide divergence among the E2 sequences from the CSF of the patient. These data suggest that GBV-C may be able to penetrate the blood-brain barrier and colonize the CNS of HIV-infected patients. However, the exact mechanisms and potential effect of the infected GBV-C in CNS on HIV-associated neuropathy needs to be further explored.
Asunto(s)
Infecciones por Flaviviridae/líquido cefalorraquídeo , Virus GB-C/genética , Infecciones por VIH/complicaciones , Hepatitis Viral Humana/líquido cefalorraquídeo , ARN Viral/genética , Carga Viral , Adulto , China , Coinfección/microbiología , Coinfección/parasitología , Coinfección/virología , Infecciones por Flaviviridae/virología , Hongos/fisiología , Virus GB-C/clasificación , Virus GB-C/aislamiento & purificación , VIH-1/fisiología , Hepatitis Viral Humana/virología , Humanos , Encefalitis Infecciosa/microbiología , Masculino , Datos de Secuencia Molecular , Filogenia , ARN Viral/metabolismo , Análisis de Secuencia de ARN , Toxoplasma/fisiología , Toxoplasmosis Cerebral/parasitología , Viremia/líquido cefalorraquídeo , Viremia/virologíaRESUMEN
Aim of this study was to estimate the prevalence of cerebrospinal fluid (CSF)/Plasma HIV-1 RNA discordance in virologically suppressed individuals presenting with incident neurologic symptoms.In this retrospective cohort study conducted between March 1, 2009, and March 1, 2017, HIV-1 infected adults exposed to atleast 12 months of antiretroviral therapy (ART) and having plasma viral load (VL) <1000âcopies/mL (virologically suppressed) were included. Among these, individuals presenting with neurologic symptoms during follow-up were assessed for CSF/Plasma HIV-1 RNA discordance by measuring HIV-1 RNA in collected plasma and CSF samples. CSF/plasma HIV-1 RNA discordance was defined as either detectable CSF HIV-1 RNA (VLâ>â20âcopies/mL) with an undetectable plasma RNA (complete viral suppression, VL ≤20âcopies/mL) or CSF HIV-1 RNAâ≥â0.5 log10 higher than plasma RNA when plasma VL was between 20 and 1000âcopies/mL (low-level viremia, LLV).Out of 1584 virologically suppressed patients, 71 (4.4%) presented with incident neurologic symptoms. Twenty out of 71 (28.2%) patients were diagnosed with CSF/Plasma HIV-1 discordance. Median plasma and CSF VL in patients with discordance was 120 [interquartile range (IQR): <20 to 332.5] and 4250 (IQR: 2550.0- 9615.0) copies/mL, respectively. All 9 individuals in which CSF HIV-1 genotypic resistance testing was done showed mutations that would compromise efficacy of prescribed ART regimen. Prevalence of CSF/plasma HIV-1 RNA discordance was higher among neurologically symptomatic patients with plasma LLV as compared with those with complete viral suppression (70% vs 11.8%, Pâ<â.001). The risk of discordance was also greater in patients who received protease inhibitor (PI) containing ART (Pâ<â.001) and those on ART regimens with central nervous system (CNS) penetration effectiveness (CPE) value <6 (Pâ=â.006).CSF/plasma HIV-1 RNA discordance indicates replication of HIV-1 that has adapted to the CNS or has developed antiretroviral drug resistance. Larger studies should be performed to study incidence of discordance in India. This will help in managing patients presenting with neurologic symptoms on suppressive ART with appropriate neuroeffective therapy.
Asunto(s)
Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , ARN Viral/sangre , ARN Viral/líquido cefalorraquídeo , Viremia/epidemiología , Adulto , Fármacos Anti-VIH/uso terapéutico , Enfermedades del Sistema Nervioso Central/virología , Femenino , Infecciones por VIH/virología , Humanos , India/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Retrospectivos , Carga Viral , Viremia/sangre , Viremia/líquido cefalorraquídeoRESUMEN
The central nervous system (CNS) is an important target of HIV, and cerebrospinal fluid (CSF) can provide a window into host-virus interactions within the CNS. The goal of this study was to determine whether HIV-specific CD8(+) T cells are present in CSF of HIV controllers (HC), who maintain low to undetectable plasma viremia without antiretroviral therapy (ART). CSF and blood were sampled from 11 HC, defined based on plasma viral load (VL) consistently below 2,000 copies/ml without ART. These included nine elite controllers (EC, plasma VL <40 copies/ml) and two viremic controllers (VC, VL 40-2,000 copies/ml). All controllers had CSF VL <40 copies/ml. Three comparison groups were also sampled: six HIV noncontrollers (NC, VL >10,000 copies/ml, no ART); seven individuals with viremia suppressed due to ART (Tx, VL <40 copies/ml); and nine HIV-negative controls. CD4(+) and CD8(+) T cells in CSF and blood were analyzed by flow cytometry to assess expression of CCR5, activation markers CD38 and HLA-DR, and memory/effector markers CD45RA and CCR7. HIV-specific CD8(+) T cells were quantified by major histocompatibility complex class I multimer staining. HIV-specific CD8(+) T cells were detected ex vivo at similar frequencies in CSF of HC and noncontrollers; the highest frequencies were in individuals with CD4 counts below 500 cells/µl. The majority of HIV-specific CD8(+) T cells in CSF were effector memory cells expressing CCR5. Detection of these cells in CSF suggests active surveillance of the CNS compartment by HIV-specific T cells, including in individuals with long-term control of HIV infection in the absence of therapy.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Resistencia a la Enfermedad/genética , Infecciones por VIH/inmunología , Interacciones Huésped-Patógeno , ARN Viral/inmunología , Viremia/inmunología , ADP-Ribosil Ciclasa 1/genética , ADP-Ribosil Ciclasa 1/inmunología , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Linfocitos T CD8-positivos/virología , Expresión Génica , Infecciones por VIH/líquido cefalorraquídeo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/genética , VIH-1/inmunología , Antígenos HLA-DR/genética , Antígenos HLA-DR/inmunología , Humanos , Antígenos Comunes de Leucocito/genética , Antígenos Comunes de Leucocito/inmunología , Activación de Linfocitos , Receptores CCR5/genética , Receptores CCR5/inmunología , Receptores CCR7/genética , Receptores CCR7/inmunología , Carga Viral/efectos de los fármacos , Carga Viral/genética , Viremia/líquido cefalorraquídeo , Viremia/tratamiento farmacológico , Viremia/virologíaRESUMEN
Placebo-controlled field efficacy trials of new Japanese encephalitis (JE) vaccines may be impractical. Therefore, an animal model to evaluate efficacy of candidate JE vaccines is sought. Previous work has shown that exposure of monkeys to JE virus (JEV) via the intranasal route results in encephalitis. Here we report the further development of this model and the availability of titered virus stocks to assess the protective efficacy of JE vaccines. To determine the effective dose of our JE challenge virus, dilutions of a stock JEV (KE-93 isolate) were inoculated into four groups of three rhesus monkeys. A dose-dependent response was observed and the 50% effective dose (ED50) was determined to be 6.0 x 10(7) plaque forming units (pfu). Among animals that developed encephalitis, clinical signs occurred 9-14 days postinoculation. Infection with JEV was confirmed by detection of JEV in nervous tissues and IgM to JEV in the cerebrospinal fluid. Viremia with JEV was also detected intermittently throughout infection. Validation of the model was performed using a known effective JE vaccine and saline control. One ED90 of virus (2.0 x 10(9) pfu) was used as a challenge dose. Four of four animals that received saline control developed encephalitis while one of four monkeys administered the JE vaccine did so. This study demonstrates that the virus strain, route of inoculation, dose, and the outcome measure (encephalitis) are suitable for assessment of protective efficacy of candidate JE vaccines.
Asunto(s)
Modelos Animales de Enfermedad , Virus de la Encefalitis Japonesa (Especie)/inmunología , Encefalitis Japonesa/prevención & control , Macaca mulatta , Vacunas Virales/normas , Administración Intranasal , Animales , Animales Lactantes , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/líquido cefalorraquídeo , Cartilla de ADN/química , ADN Viral/química , Electroforesis en Gel de Agar , Virus de la Encefalitis Japonesa (Especie)/patogenicidad , Encefalitis Japonesa/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Pruebas de Inhibición de Hemaglutinación , Inmunización , Masculino , Ratones , Pruebas de Neutralización , ARN Viral/análisis , ARN Viral/sangre , ARN Viral/líquido cefalorraquídeo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Vacunas Virales/administración & dosificación , Vacunas Virales/inmunología , Viremia/líquido cefalorraquídeoRESUMEN
Human Cytomegalovirus (HCVM) encodes several G-protein coupled receptors, such as US28 protein. We determined the US28 gene sequence from clinical isolates obtained from 17 Human Immunodeficiency Virus (HIV)-infected patients with HCMV infection. Two types of clinical specimens were collected: peripheral blood leucocytes (PBLs) from 12 patients with HCMV-positive viremia and cerebro-spinal fluids (CSF) from five patients with HCMV-encephalitis. Comparison of US28 nucleotide sequences between clinical specimens and several HCMV reference strains showed that mutations were clustered at both ends of the gene. The mutations observed at the C-terminus were observed at some sequences whereas the mutations observed at the N-terminus lead us to define five patterns of mutations. These patterns were equally distributed among isolates obtained from CSF or PBLs of HIV-infected patients. For each clinical isolate, the gB genotype was determined. There was no genetic association between gB genotype and US28 patterns. The comparison of the results of the present study and those published from sequences obtained from children with HCMV congenital disease (Arav-Boger, 2002) demonstrates that two motifs appear especifically either in US28 protein sequences obtained from HIV-positive patients (motif 4) or in US28 protein sequences obtained from patients with congenital HCMV infection (motif 5/genotype B). The appearance of these patterns of mutations in other clinical context needs to be studied.
Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/virología , Infecciones por Citomegalovirus/virología , Citomegalovirus/genética , Variación Genética , Receptores de Quimiocina/genética , Proteínas Virales/genética , Infecciones Oportunistas Relacionadas con el SIDA/sangre , Infecciones Oportunistas Relacionadas con el SIDA/líquido cefalorraquídeo , Secuencia de Aminoácidos , Citomegalovirus/aislamiento & purificación , Infecciones por Citomegalovirus/sangre , Infecciones por Citomegalovirus/líquido cefalorraquídeo , Encefalitis Viral/sangre , Encefalitis Viral/líquido cefalorraquídeo , Encefalitis Viral/virología , Humanos , Datos de Secuencia Molecular , Mutación , Receptores de Quimiocina/química , Proteínas Virales/química , Viremia/sangre , Viremia/líquido cefalorraquídeo , Viremia/virologíaRESUMEN
OVERVIEW: In newborns with symptomatic congenital cytomegalovirus (CMV) infection, neuroimaging is the best available predictor of neurodevelopmental outcome. Cerebrospinal fluid (CSF) findings in congenital CMV infection have seldom been described. Neonates with central nervous system infections present high CSF Beta(2)-microglobulin (beta(2)-m) levels. OBJECTIVES: The objectives of this study were: (1) to determine whether CSF beta(2)-m is increased in newborns with symptomatic congenital CMV infection, and (2) to examine its correlation with neuroimaging findings. MATERIALS AND METHODS: Fourteen newborns with symptomatic congenital CMV infection admitted to La Paz Hospital from 1990 through 2004 underwent determination of CSF beta(2)-m. Ninety-three newborns, constituting the comparison group, underwent CSF beta(2)-m determination as part of a sepsis or meningo/encephalitis work-up, and at discharge had sterile cultures and normal neurological status. Neuroimaging findings were scored according to a semiquantitative system: (0) no abnormalities; (1) single punctate periventricular (PV) calcification and/or hyperechogenic areas in the thalamus and basal ganglia; (2) multiple discrete PV calcifications and/or ventriculomegaly; and (3) extensive PV calcifications and/or brain atrophy. DISCUSSION AND CONCLUSION: CSF beta(2)-m was increased in newborns with CMV infection (median 6.21 mg/L) compared with controls (1.68 mg/L) (P<.001). beta(2)-m showed a correlation with neuroimaging scores (r (s)=0.753, P=.002). beta(2)-m was higher in patients who scored 2-3 (12.83 mg/L) than in patients who scored 0-1 (5.52 mg/L) (P=.028). CSF beta(2)-m is increased in newborns with symptomatic congenital CMV infection and correlates with neuroimaging abnormalities. beta(2)-m appears to be an indicator of the severity of brain involvement in congenital CMV infection.
Asunto(s)
Infecciones por Citomegalovirus/líquido cefalorraquídeo , Infecciones por Citomegalovirus/congénito , Imagen por Resonancia Magnética , Tomografía Computarizada por Rayos X , Ultrasonografía Doppler Transcraneal , Microglobulina beta-2/líquido cefalorraquídeo , Puntaje de Apgar , Encéfalo/anomalías , Encéfalo/virología , Encefalopatías/líquido cefalorraquídeo , Encefalopatías/diagnóstico , Encefalopatías/virología , Calcinosis/líquido cefalorraquídeo , Calcinosis/virología , Estudios de Casos y Controles , Infecciones del Sistema Nervioso Central/líquido cefalorraquídeo , Infecciones del Sistema Nervioso Central/diagnóstico , Infecciones del Sistema Nervioso Central/virología , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/diagnóstico , Femenino , Estudios de Seguimiento , Humanos , Recién Nacido , Masculino , Meningoencefalitis/líquido cefalorraquídeo , Meningoencefalitis/virología , Proyectos de Investigación , Índice de Severidad de la Enfermedad , España , Viremia/líquido cefalorraquídeo , Viremia/virologíaRESUMEN
In a prospective study during the summer and fall of 1982, enterovirus was isolated from 48 hospitalized children; in 29 (60%) enterovirus was isolated from CSF or blood, and in 19 (40%) only a presumptive diagnosis was established. Blood was positive in 21 (44%) and was the only positive specimen in two children. A presumptive diagnosis was provided within 4 days of admission in 38 (80%) and within 48 hours in 19 (40%) of the children from whom enterovirus was isolated. Viremia was most often detected in febrile infants younger than 3 months of age with a clinical picture simulating bacterial sepsis. The presence of viremia was inversely related to the presence of CSF pleocytosis and to virus isolation from CSF. The diagnosis of diseases caused by enterovirus is more accurate when blood culture is added to CSF stool and throat cultures.
Asunto(s)
Infecciones por Enterovirus/microbiología , Viremia/microbiología , Adolescente , Niño , Preescolar , Infecciones por Coxsackievirus/microbiología , Diagnóstico Diferencial , Infecciones por Echovirus/microbiología , Enterovirus/aislamiento & purificación , Infecciones por Enterovirus/líquido cefalorraquídeo , Heces/microbiología , Hospitalización , Humanos , Lactante , Recién Nacido , Meningitis/microbiología , Monocitos/microbiología , Faringe/microbiología , Estudios Prospectivos , Sepsis/microbiología , Viremia/líquido cefalorraquídeoAsunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Lamivudine/uso terapéutico , Mutación/genética , Organofosfonatos/uso terapéutico , Viremia/sangre , Viremia/líquido cefalorraquídeo , Zidovudina/uso terapéutico , Adenina/uso terapéutico , Estudios de Cohortes , Combinación de Medicamentos , Quimioterapia Combinada , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Estudios Prospectivos , Tenofovir , Viremia/tratamiento farmacológicoRESUMEN
UNLABELLED: Combination antiretroviral therapy with ritonavir and saquinavir has established potent and durable activity on plasma viremia. CNS HIV infection may be sequestered from drug therapy that does not penetrate the blood-brain barrier. Penetration of these protease inhibitors into the cerebrospinal fluid (CSF) and CSF HIV RNA levels on such therapy has not been well described. DESIGN/METHODS: In a cross-sectional study, 28 HIV1-infected study subjects were evaluated either before initiation of or before maximal response to ritonavir-saquinavir therapy, during maximal plasma virologic response, and after virologic failure. Simultaneous samples of plasma and cerebrospinal fluid were obtained from 24 study subjects to measure HIV RNA and protease inhibitor levels. RESULTS: Across the treatment groups, a strong correlation was found between plasma and CSF HIV RNA levels (r = 0.870; p < .001). In each study subject with plasma HIV RNA levels below assay limit (80 copies/ml), the CSF HIV RNA level was also below the limit of quantitation. Low levels of saquinavir (<2 ng/ml) and ritonavir (<25 ng/ml) in the CSF were observed, with a CSF:plasma drug concentration ratio of < or = 0.005 (0.5%) in all study subjects evaluated (n = 11). The plasma:CSF HIV RNA ratio was high before or early in treatment (median, 38; interquartile range [IQR], 13,97), but low (median, 0.29; IQR, 0.17, 7.5) in those failing therapy (group C, p < .001). CONCLUSIONS: CSF ritonavir and saquinavir levels are consistent with the estimated known fraction of unbound drug in plasma (<2%). Across these treatment response groups, suppression of plasma viremia can predict low CSF HIV RNA levels. This correlation may represent HIV RNA transport and equilibrium between CSF and plasma, or it may represent CNS anti-HIV activity of protease inhibitors. The low drug levels and inverted ratio of HIV RNA in the CSF compared with plasma early in plasma virologic breakthrough suggests CSF virologic failure may contribute to failure of plasma virologic response.