RESUMEN
A large portion of life cycle transportation impacts occur during vehicle operation, and key improvement strategies include increasing powertrain efficiency, vehicle electrification, and lightweighting vehicles by reducing their mass. The potential energy benefits of vehicle lightweighting are large, given that 29.5 EJ was used in all modes of U.S. transportation in 2016, and roughly half of the energy spent in wheeled transportation and the majority of energy spent in aircraft is used to move vehicle mass. We collect and review previous work on lightweighting, identify key parameters affecting vehicle environmental performance (e.g., vehicle mode, fuel type, material type, and recyclability), and propose a set of 10 principles, with examples, to guide environmental improvement of vehicle systems through lightweighting. These principles, based on a life cycle perspective and taken as a set, allow a wide range of stakeholders (designers, policy-makers, and vehicle manufacturers and their material and component suppliers) to evaluate the trade-offs inherent in these complex systems. This set of principles can be used to evaluate trade-offs between impact categories and to help avoid shifting of burdens to other life cycle phases in the process of improving use-phase environmental performance.
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Transportes , Emisiones de Vehículos , Vehículos a Motor , Fenómenos FísicosRESUMEN
Mutations in the transcription factor GATA2 underlie the syndrome of monocytopenia and B- and natural killer (NK)-cell lymphopenia associated with opportunistic infections and cancers. In addition, patients have recurrent and severe viral infections. NK cells play a critical role in mediating antiviral immunity. Human NK cells are thought to mature in a linear fashion, with the CD56(bright) stage preceding terminal maturation to the CD56(dim) stage, considered the most enabled for cytotoxicity. Here we report an NK cell functional defect in GATA2-deficient patients and extend this genetic lesion to what is considered to be the original NK cell-deficient patient. In most cases, GATA2 deficiency is accompanied by a severe reduction in peripheral blood NK cells and marked functional impairment. The NK cells detected in peripheral blood of some GATA2-deficient patients are exclusively of the CD56(dim) subset, which is recapitulated on in vitro NK cell differentiation. In vivo, interferon α treatment increased NK cell number and partially restored function but did not correct the paucity of CD56(bright) cells. Thus, GATA2 is required for the maturation of human NK cells and the maintenance of the CD56(bright) pool in the periphery. Defects in GATA2 are a novel cause of profound NK cell dysfunction.
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Antígeno CD56/inmunología , Diferenciación Celular/inmunología , Factor de Transcripción GATA2/genética , Células Asesinas Naturales/inmunología , Linfopenia/genética , Antígenos CD34/metabolismo , Antígeno CD56/metabolismo , Citotoxicidad Inmunológica/inmunología , Factor de Transcripción GATA2/inmunología , Factor de Transcripción GATA2/metabolismo , Humanos , Inmunofenotipificación , Células K562 , Células Asesinas Naturales/citología , Células Asesinas Naturales/metabolismo , Activación de Linfocitos/inmunología , Recuento de Linfocitos , Linfopenia/inmunología , Linfopenia/metabolismo , Células del Estroma/citología , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismoRESUMEN
This study examines the vehicle-cycle and vehicle total life-cycle impacts of substituting lightweight materials into vehicles. We determine part-based greenhouse gas (GHG) emission ratios by collecting material substitution data and evaluating that alongside known mass-based GHG ratios (using and updating Argonne National Laboratory's GREET model) associated with material pair substitutions. Several vehicle parts are lightweighted via material substitution, using substitution ratios from a U.S. Department of Energy report, to determine GHG emissions. We then examine fuel-cycle GHG reductions from lightweighting. The fuel reduction value methodology is applied using FRV estimates of 0.15-0.25, and 0.25-0.5 L/(100km·100 kg), with and without powertrain adjustments, respectively. GHG breakeven values are derived for both driving distance and material substitution ratio. While material substitution can reduce vehicle weight, it often increases vehicle-cycle GHGs. It is likely that replacing steel (the dominant vehicle material) with wrought aluminum, carbon fiber reinforced plastic (CRFP), or magnesium will increase vehicle-cycle GHGs. However, lifetime fuel economy benefits often outweigh the vehicle-cycle, resulting in a net total life-cycle GHG benefit. This is the case for steel replaced by wrought aluminum in all assumed cases, and for CFRP and magnesium except for high substitution ratio and low FRV.
Asunto(s)
Vehículos a Motor , Emisiones de Vehículos/análisis , Aluminio , Carbono , Fibra de Carbono , Efecto Invernadero , Modelos Teóricos , Plásticos , AceroRESUMEN
Lightweighting is a key strategy to improve vehicle fuel economy. Assessing the life-cycle benefits of lightweighting requires a quantitative description of the use-phase fuel consumption reduction associated with mass reduction. We present novel methods of estimating mass-induced fuel consumption (MIF) and fuel reduction values (FRVs) from fuel economy and dynamometer test data in the U.S. Environmental Protection Agency (EPA) database. In the past, FRVs have been measured using experimental testing. We demonstrate that FRVs can be mathematically derived from coast down coefficients in the EPA vehicle test database avoiding additional testing. MIF and FRVs calculated for 83 different 2013 MY vehicles are in the ranges 0.22-0.43 and 0.15-0.26 L/(100 km 100 kg), respectively, and increase to 0.27-0.53 L/(100 km 100 kg) with powertrain resizing to retain equivalent vehicle performance. We show how use-phase fuel consumption can be estimated using MIF and FRVs in life cycle assessments (LCAs) of vehicle lightweighting from total vehicle and vehicle component perspectives with, and without, powertrain resizing. The mass-induced fuel consumption model is illustrated by estimating lifecycle greenhouse gas (GHG) emission benefits from lightweighting a grille opening reinforcement component using magnesium or carbon fiber composite for 83 different vehicle models.
Asunto(s)
Gasolina/análisis , Modelos Teóricos , Vehículos a Motor , Efecto Invernadero , Magnesio/química , Acero/química , Emisiones de Vehículos/análisisRESUMEN
Memory T cells cross-reactive with epitopes encoded by related or even unrelated viruses may alter the immune response and pathogenesis of infection by a process known as heterologous immunity. Because a challenge virus epitope may react with only a subset of the T cell repertoire in a cross-reactive epitope-specific memory pool, the vigorous cross-reactive response may be narrowly focused, or oligoclonal. We show in this article, by examining human T cell cross-reactivity between the HLA-A2-restricted influenza A virus-encoded M1(58-66) epitope (GILGFVFTL) and the dissimilar Epstein-Barr virus-encoded BMLF1(280-288) epitope (GLCTLVAML), that, under some conditions, heterologous immunity can lead to a significant broadening, rather than a narrowing, of the TCR repertoire. We suggest that dissimilar cross-reactive epitopes might generate a broad, rather than a narrow, T cell repertoire if there is a lack of dominant high-affinity clones; this hypothesis is supported by computer simulation.
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Epítopos de Linfocito T/metabolismo , Herpesvirus Humano 4/inmunología , Herpesvirus Humano 4/metabolismo , Virus de la Influenza A/inmunología , Virus de la Influenza A/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Adolescente , Adulto , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/virología , Células Clonales , Reacciones Cruzadas , Antígeno HLA-A2/inmunología , Antígeno HLA-A2/metabolismo , Humanos , Epítopos Inmunodominantes/metabolismo , Persona de Mediana Edad , Oligopéptidos/inmunología , Oligopéptidos/metabolismo , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/metabolismo , Proteínas de la Matriz Viral/inmunología , Proteínas de la Matriz Viral/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Understanding the properties of HIV-1 variants that are transmitted from women to their infants is crucial to improving strategies to prevent transmission. In this study, 162 full-length envelope (env) clones were generated from plasma RNA obtained from 5 HIV-1 Clade B infected mother-infant pairs. Following extensive genotypic and phylogenetic analyses, 35 representative clones were selected for functional studies. RESULTS: Infant quasispecies were highly homogeneous and generally represented minor maternal variants, consistent with transmission across a selective bottleneck. Infant clones did not differ from the maternal in env length, or glycosylation. All infant variants utilized the CCR5 co-receptor, but were not macrophage tropic. Relatively high levels (IC50 ≥ 100 µg/ml) of autologous maternal plasma IgG were required to neutralize maternal and infant viruses; however, all infant viruses were neutralized by pooled sera from HIV-1 infected individuals, implying that they were not inherently neutralization-resistant. All infant viruses were sensitive to the HIV-1 entry inhibitors Enfuvirtide and soluble CD4; none were resistant to Maraviroc. Sensitivity to human monoclonal antibodies 4E10, 2F5, b12 and 2G12 varied. CONCLUSIONS: This study provides extensive characterization of the genotypic and functional properties of HIV-1 env shortly after transmission. We present the first detailed comparisons of the macrophage tropism of infant and maternal env variants and their sensitivity to Maraviroc, the only CCR5 antagonist approved for therapeutic use. These findings may have implications for improving approaches to prevent mother-to-child HIV-1 transmission.
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Infecciones por VIH/virología , VIH-1/genética , Enfermedades del Recién Nacido/virología , Transmisión Vertical de Enfermedad Infecciosa , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen env del Virus de la Inmunodeficiencia Humana/metabolismo , Adulto , Femenino , Infecciones por VIH/inmunología , Infecciones por VIH/transmisión , VIH-1/clasificación , VIH-1/aislamiento & purificación , VIH-1/metabolismo , Humanos , Lactante , Recién Nacido , Enfermedades del Recién Nacido/inmunología , Masculino , Datos de Secuencia Molecular , Filogenia , Receptores CCR5/inmunologíaRESUMEN
BACKGROUND: Massachusetts began newborn screening (NBS) for severe combined immunodeficiency (SCID) using measurement of T-cell receptor excision circles (TRECs) from dried blood spots. OBJECTIVE: We describe developments and outcomes from the first 10 years of this program (February 1, 2009, to January 31, 2019). METHODS: TREC values, diagnostic, and outcome data from all patients screened for SCID were evaluated. RESULTS: NBS of 720,038 infants prompted immunologic evaluation of 237 (0.03%). Of 237, 9 were diagnosed with SCID/leaky SCID (4% of referrals vs 0.001% general population). Another 7 were diagnosed with other combined immunodeficiencies, and 3 with athymia. SCID/leaky SCID incidence was approximately 1 in 80,000, whereas approximately 1 in 51,000 had severe T-cell lymphopenia for which definitive treatment was indicated. All patients with SCID/leaky SCID underwent hematopoietic cell transplant or gene therapy with 100% survival. One patient with athymia underwent successful thymus transplant. No known cases of SCID were missed. Compared with outcomes from the 10 years before SCID NBS, survival trended higher (9 of 9 vs 4 of 7), likely due to a lower rate of infection before treatment. CONCLUSIONS: Our data support a single NBS testing-and-referral algorithm for all gestational ages. Despite lower median TREC values in premature infants, the majority for all ages are well above the TREC cutoff and the algorithm, which selects urgent (undetectable TREC) and repeatedly abnormal TREC values, minimizes referral. We also found that low naïve T-cell percentage is associated with a higher risk of SCID/CID, demonstrating the utility of memory/naïve T-cell phenotyping as part of follow-up flow cytometry.
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Trasplante de Células Madre Hematopoyéticas , Inmunodeficiencia Combinada Grave , Humanos , Lactante , Recién Nacido , Recien Nacido Prematuro , Massachusetts/epidemiología , Tamizaje Neonatal , Receptores de Antígenos de Linfocitos T/genética , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/epidemiología , Inmunodeficiencia Combinada Grave/genéticaRESUMEN
Spike (S) proteins of coronaviruses, including the coronavirus that causes severe acute respiratory syndrome (SARS), associate with cellular receptors to mediate infection of their target cells. Here we identify a metallopeptidase, angiotensin-converting enzyme 2 (ACE2), isolated from SARS coronavirus (SARS-CoV)-permissive Vero E6 cells, that efficiently binds the S1 domain of the SARS-CoV S protein. We found that a soluble form of ACE2, but not of the related enzyme ACE1, blocked association of the S1 domain with Vero E6 cells. 293T cells transfected with ACE2, but not those transfected with human immunodeficiency virus-1 receptors, formed multinucleated syncytia with cells expressing S protein. Furthermore, SARS-CoV replicated efficiently on ACE2-transfected but not mock-transfected 293T cells. Finally, anti-ACE2 but not anti-ACE1 antibody blocked viral replication on Vero E6 cells. Together our data indicate that ACE2 is a functional receptor for SARS-CoV.
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Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/metabolismo , Enzima Convertidora de Angiotensina 2 , Animales , Anticuerpos/inmunología , Anticuerpos/farmacología , Carboxipeptidasas/antagonistas & inhibidores , Carboxipeptidasas/genética , Carboxipeptidasas/inmunología , Carboxipeptidasas/metabolismo , Línea Celular , Chlorocebus aethiops , Células Gigantes/citología , Células Gigantes/metabolismo , Humanos , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Peso Molecular , Peptidil-Dipeptidasa A/inmunología , Peptidil-Dipeptidasa A/metabolismo , Unión Proteica , Estructura Terciaria de Proteína , Receptores Virales/antagonistas & inhibidores , Receptores Virales/genética , Receptores Virales/inmunología , Receptores Virales/metabolismo , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/genética , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/crecimiento & desarrollo , Solubilidad , Glicoproteína de la Espiga del Coronavirus , Transfección , Células Vero , Proteínas del Envoltorio Viral/química , Proteínas del Envoltorio Viral/genética , Proteínas del Envoltorio Viral/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
The marked proliferation of activated CD8+ T cells is pathognomonic of EBV-associated infectious mononucleosis (IM), common in young adults. Since the diversity and size of the memory CD8+ T cell population increase with age, we questioned whether IM was mediated by the reactivation of memory CD8+ T cells specific to previously encountered pathogens but cross-reactive with EBV. Of 8 HLA-A2+ IM patients, 5 had activated T cells specific to another common virus, as evidenced by a significantly higher number of peripheral blood influenza A virus M1(58-66)-specific T cells compared with healthy immune donors. Two patients with an augmented M1 response had tetramer-defined cross-reactive cells recognizing influenza M1 and EBV-BMLF1(280-288), which accounted for up to one-third of their BMLF1-specific population and likely contributed to a skewed M1-specific T cell receptor repertoire. These epitopes, with only 33% sequence similarity, mediated differential effects on the function of the cross-reactive T cells, which may contribute to alterations in disease outcome. EBV could potentially encode an extensive pool of T cell epitopes that activate other cross-reactive memory T cells. Our results support the concept that cross-reactive memory CD8+ T cells activated by EBV contribute to the characteristic lymphoproliferation of IM.
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Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/virología , Herpesvirus Humano 4/metabolismo , Mononucleosis Infecciosa/virología , Linfocitos/citología , Linfocitos/virología , Orthomyxoviridae/genética , Adolescente , Adulto , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Proliferación Celular , Quimiocina CCL4 , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Epítopos/química , Citometría de Flujo , Genes MHC Clase I , Antígeno HLA-A2/química , Humanos , Memoria Inmunológica , Virus de la Influenza A/inmunología , Interferón gamma/metabolismo , Células K562 , Leucocitos Mononucleares/citología , Activación de Linfocitos , Proteínas Inflamatorias de Macrófagos/metabolismo , Péptidos/química , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T/inmunología , Linfocitos T/virología , Factores de TiempoAsunto(s)
Herpesvirus Humano 4 , Mononucleosis Infecciosa , Adolescente , Corticoesteroides/uso terapéutico , Anticuerpos Antivirales/sangre , Antivirales/uso terapéutico , Diagnóstico Diferencial , Femenino , Herpesvirus Humano 4/inmunología , Humanos , Mononucleosis Infecciosa/complicaciones , Mononucleosis Infecciosa/diagnóstico , Mononucleosis Infecciosa/terapia , Masculino , Faringitis/microbiología , Infecciones Estreptocócicas/diagnóstico , Streptococcus pyogenesRESUMEN
Composites of single-walled carbon nanotubes (SWNTs) and water-soluble polymers (WSP) are the focus of significant worldwide research due to a number of applications in biotechnology and photonics, particularly for ultrashort pulse generation. Despite the unique possibility of constructing non-linear optical SWNT-WSP composites with controlled optical properties, their thermal degradation threshold and limit of operational power remain unexplored. In this study, we discover the nature of the SWNT-polyvinyl alcohol (PVA) film thermal degradation and evaluate the modification of the composite properties under continuous high-power ultrashort pulse laser operation. Using high-precision optical microscopy and micro-Raman spectroscopy, we have examined SWNT-PVA films before and after continuous laser radiation exposure (up to 40 hours) with a maximum optical fluence of 2.3 mJ·cm-2. We demonstrate that high-intensity laser radiation results in measurable changes in the composition and morphology of the SWNT-PVA film due to efficient heat transfer from SWNTs to the polymer matrix. The saturable absorber modification does not affect the laser operational performance. We anticipate our work to be a starting point for more sophisticated research aimed at the enhancement of SWNT-PVA films fabrication for their operation as reliable saturable absorbers in high-power ultrafast lasers.
RESUMEN
Mother-to-child transmission (MTCT) of HIV-1 is the major mode of paediatric infection. The rapidly increasing incidence of MTCT worldwide has resulted in an urgent need for preventive strategies. Antiretroviral regimens can prevent intrapartum HIV transmission; however, these regimens do not prevent HIV transmission through breastfeeding. Furthermore, children who escape MTCT are again at risk of infection when they become sexually active as adolescents. An infant vaccine regimen, begun at birth, would hence be a more attractive strategy and might also provide the basis for lifetime protection. Unique features of MTCT and paediatric HIV disease could be helpful in understanding correlates of immune protection and could facilitate rapid assessment of vaccine efficacy. Thus, there is compelling rationale to develop safe, effective HIV vaccines for use in infants and children. Here, we discuss the scientific and logistical challenges for the development of paediatric HIV vaccines; available vaccines and completed or planned paediatric vaccine trials are also discussed.
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Vacunas contra el SIDA/administración & dosificación , Infecciones por VIH , VIH-1/inmunología , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Leche Humana/virología , Pediatría , Adolescente , Adulto , África del Sur del Sahara/epidemiología , Animales , Femenino , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , Infecciones por VIH/transmisión , Humanos , Lactante , Prevalencia , Proteínas Recombinantes/inmunologíaRESUMEN
BACKGROUND: Depletion of CD4 T-cell counts or progression of human immunodeficiency virus (HIV) disease occurs rapidly in children, but few data address the efficacy of aggressive therapy for HIV-infected children. METHODS: We evaluated the safety, tolerability, and activity of three regimens of antiretroviral therapy in a multicenter, open-label, phase 1-2 trial. Children infected with HIV type 1 (HIV-1) were stratified at entry according to age--three months or younger (early therapy) or older than three months (delayed therapy)--and assigned sequentially to one of three regimens. Children continued to receive treatment for up to 200 weeks if the plasma HIV-1 RNA level was less than 1000 copies per milliliter by 16 weeks. RESULTS: Plasma HIV-1 RNA levels fell from a median of 5.3 log copies per milliliter (range, 3.3 to 6.4 log copies per milliliter) at baseline to less than 1000 copies per milliliter at 16 weeks in 32 of 52 infants (62 percent). Plasma HIV-1 RNA levels were below 400 copies per milliliter at 48 weeks in 26 infants (50 percent) and at 200 weeks in 23 infants (44 percent). An intention-to-treat analysis revealed that significantly more children who received stavudine, lamivudine, nevirapine, and nelfinavir had plasma HIV-1 RNA levels of less than 400 copies per milliliter at 48 weeks (83 percent) and 200 weeks (72 percent) than children who received reverse-transcriptase inhibitors alone (P=0.001 and P=0.01, respectively). Fewer infants in the delayed-therapy group than in the early-therapy group (30 percent vs. 60 percent) had plasma HIV-1 RNA levels of less than 400 copies per milliliter at 200 weeks (P=0.03). Treatment-associated adverse effects were infrequent. CONCLUSIONS: In this phase 1-2 trial involving HIV-1-infected children, an age of three months or younger at the initiation of therapy and treatment with stavudine, lamivudine, nevirapine, and nelfinavir were associated with improved long-term viral suppression. Larger, randomized trials are required to define the optimal time to initiate therapy and the optimal regimen for these infants.
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Antirretrovirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/fisiología , Replicación Viral/efectos de los fármacos , Antirretrovirales/farmacología , Recuento de Linfocito CD4 , Distribución de Chi-Cuadrado , Preescolar , Farmacorresistencia Viral/genética , Quimioterapia Combinada , Femenino , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/genética , Humanos , Lactante , Modelos Logísticos , Masculino , Mutación , ARN Viral/sangre , Carga ViralRESUMEN
BACKGROUND: Rates of mother-to-child transmission of HIV-1 (MTCT) have historically been lower in European than in American cohort studies, possibly due to differences in population characteristics. The Pediatric AIDS Clinical Trials Group Protocol (PACTG) 316 trial evaluated the effectiveness of the addition of intrapartum/neonatal nevirapine in reducing MTCT in women already receiving antiretroviral prophylaxis. Participation of large numbers of pregnant HIV-infected women from the US and Western Europe enrolling in the same clinical trial provided the opportunity to identify and explore differences in their characteristics and in the use of non-study interventions to reduce MTCT. METHODS: In this secondary analysis, 1350 women were categorized according to enrollment in centres in the USA (n = 978) or in Europe (n = 372). Factors associated with receipt of highly active antiretroviral therapy and with elective caesarean delivery were identified with logistic regression. RESULTS: In Europe, women enrolled were more likely to be white and those of black race were mainly born in Sub-Saharan Africa. Women in the US were younger and more likely to have previous pregnancies and miscarriages and a history of sexually transmitted infections. More than 90% of women did not report symptoms of their HIV infection; however, more women from the US had symptoms (8%), compared to women from Europe (4%). Women in the US were less likely to have HIV RNA levels <400 copies/ml at delivery than women enrolling in Europe, and more likely to receive highly active antiretroviral therapy, and to start therapy earlier in pregnancy. The elective caesarean delivery rate in Europe was 61%, significantly higher than that in the US (22%). Overall, 1.48% of infants were infected and there was no significant difference in the rate of transmission between Europe and the US despite the different approaches to treatment and delivery. CONCLUSION: These findings confirm that there are important historical differences between the HIV-infected pregnant populations in Western Europe and the USA, both in terms of the characteristics of the women and their obstetric and therapeutic management. Although highly active antiretroviral therapy predominates in pregnancy in both settings now, population differences are likely to remain. TRIAL REGISTRATION: NCT00000869.
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Terapia Antirretroviral Altamente Activa/estadística & datos numéricos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/transmisión , VIH-1/efectos de los fármacos , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Complicaciones Infecciosas del Embarazo/virología , Aborto Espontáneo , Adulto , Cesárea , Estudios de Cohortes , Europa (Continente)/epidemiología , Femenino , Edad Gestacional , Infecciones por VIH/epidemiología , Humanos , Recién Nacido , Transmisión Vertical de Enfermedad Infecciosa/estadística & datos numéricos , Embarazo , Resultado del Embarazo , Factores de Riesgo , Estados Unidos/epidemiología , Carga ViralRESUMEN
The primary aim of this study was to measure HIV-1 persistence following combination antiretroviral therapy (cART) in infants and children. Peripheral blood mononuclear cell (PBMC) HIV-1 DNA was quantified prior to and after 1 year of cART in 30 children, stratified by time of initiation (early, age <3 months, ET; late, age >3 months-2 years, LT). Pre-therapy PBMC HIV-1 DNA levels correlated with pre-therapy plasma HIV-1 levels (r = 0.59, p<0.001), remaining statistically significant (p = 0.002) after adjustment for prior perinatal antiretroviral exposure and age at cART initiation. PBMC HIV-1 DNA declined significantly after 1 year of cART (Overall: -0.91±0.08 log10 copies per million PBMC, p<0.001; ET: -1.04±0.11 log10 DNA copies per million PBMC, p<0.001; LT: -0.74 ±0.13 log10 DNA copies per million PBMC, p<0.001) but rates of decline did not differ significantly between ET and LT. HIV-1 replication exposure over the first 12 months of cART, estimated as area-under-the-curve (AUC) of circulating plasma HIV-1 RNA levels, was significantly associated with PBMC HIV-1 DNA at one year (r = 0.51, p = 0.004). In 21 children with sustained virologic suppression after 1 year of cART, PBMC HIV-1 DNA levels continued to decline between years 1 and 4 (slope -0.21 log10 DNA copies per million PBMC per year); decline slopes did not differ significantly between ET and LT. PBMC HIV-1 DNA levels at 1 year and 4 years of cART correlated with age at cART initiation (1 year: p = 0.04; 4 years: p = 0.03) and age at virologic control (1 and 4 years, p = 0.02). Altogether, these data indicate that reducing exposure to HIV-1 replication and younger age at cART initiation are associated with lower HIV-1 DNA levels at and after one year of age, supporting the concept that HIV-1 diagnosis and cART initiation in infants should occur as early as possible.
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Antirretrovirales/uso terapéutico , ADN Viral/antagonistas & inhibidores , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , ARN Viral/antagonistas & inhibidores , Replicación Viral/efectos de los fármacos , Terapia Antirretroviral Altamente Activa , Preescolar , Variaciones en el Número de Copia de ADN , ADN Viral/biosíntesis , ADN Viral/genética , Femenino , Infecciones por VIH/diagnóstico , Infecciones por VIH/virología , VIH-1/fisiología , Humanos , Lactante , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/virología , Estudios Longitudinales , Masculino , ARN Viral/biosíntesis , ARN Viral/genética , Tiempo de Tratamiento , Resultado del Tratamiento , Carga Viral/efectos de los fármacos , Replicación Viral/genéticaRESUMEN
Recent reports have determined that HIV-1 Vif counteracts an innate antiviral cellular factor, Apobec3G. However, the function of Vif during HIV-1 pathogenesis remains poorly understood. To gain a better understanding of Vif function, the viral isolate from an HIV-1-infected long-term nonprogressor (LTNP) that displayed a Vif-mutant replication phenotype was studied. This LTNP has been infected since before 1983 and has no HIV-related disease in the absence of antiretroviral therapy. From separate samples, obtained on more than one study visit, virus grew in cocultures of LTNP cells with Vif-complementing T cell lines, but not the parental T cell lines. An unusual amino acid motif (KKRK) was found in the Vif sequence at positions 90 to 93. Since this motif commonly functions as a nuclear localization sequence, experiments were performed to determine the ability of this KKRK motif to mediate nuclear localization of Vif. Wild-type Vif displayed a predominantly cytoplasmic distribution. In contrast, the KKRK Vif showed a predominantly nuclear localization. The effect of the KKRK mutation on virus production and infectivity was also studied. The KKRK motif that mislocalizes Vif to the nucleus also reduces viral replication and infectivity in nonpermissive cells. Our data highlight the importance of Vif in HIV-1 pathogenesis and also provide a unique tool to investigate the interaction of Vif and Apobec3G.
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Núcleo Celular/metabolismo , VIH-1/patogenicidad , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Línea Celular , Productos del Gen vif/química , Productos del Gen vif/genética , Productos del Gen vif/metabolismo , Sobrevivientes de VIH a Largo Plazo , VIH-1/genética , VIH-1/metabolismo , Humanos , Datos de Secuencia Molecular , Mutación , Análisis de Secuencia de ADN , Productos del Gen vif del Virus de la Inmunodeficiencia HumanaRESUMEN
HIV-1 infection is one of the leading causes of childhood morbidity and mortality globally and mother-to-child transmission (MTCT) is the major mode of infection. Over the past decade, natural history and interventional studies have improved our understanding of the pathogenesis of MTCT and pediatric HIV-1 infection. This has resulted in the development of effective preventive strategies to reduce new infections and therapeutic strategies to improve outcome following infection. However, successful implementation of these preventive and therapeutic strategies has been limited in resource-poor settings, where the majority of new pediatric infections occur. In addition, toxicities and antiretroviral resistance may limit the long-term utility of currently available strategies. Continued efforts to understand MTCT and pediatric HIV-1 pathogenesis and to refine preventive and therapeutic strategies are of high priority.
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Infecciones por VIH , VIH-1 , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Adolescente , Fármacos Anti-VIH/uso terapéutico , Niño , Preescolar , Femenino , Infecciones por VIH/fisiopatología , Infecciones por VIH/prevención & control , Infecciones por VIH/transmisión , Humanos , Lactante , Recién Nacido , Embarazo , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Complicaciones Infecciosas del Embarazo/virología , Inhibidores de la Transcriptasa Inversa/uso terapéuticoRESUMEN
The detection of replication-competent human immunodeficiency virus type 1 (HIV-1) in infected individuals is integral for studies of viral latency and reservoirs of continuing replication during treatment. We describe a modified coculture method to detect/isolate virus from HIV-1-infected individuals with low or undetectable plasma viral loads. We observed a wide range in CD4 and chemokine receptor concentrations on CD4(+) T cells of HIV-1-uninfected donors. We selected cells from donors who expressed high levels of CCR5 after mitogen stimulation to combine in culture with peripheral blood mononuclear cells of HIV-1-infected individuals. Using this donor-enhanced culture method, viruses were isolated from asymptomatic adults with longterm nonprogressive infection, and children receiving effective highly active antiretroviral therapy, whereas parallel cultures with cells expressing lower levels of CCR5 yielded none. Virus was isolated from an individual for whom all previous attempts using reported methods were unsuccessful. Virus growth from cryopreserved cells from this same individual was detected at multiple sampling time points, including a time point at which a sensitive assay to measure 2-LTR (long terminal repeat) circular forms of the viral genome was negative. This will be a useful technique by which to study viral latency and HIV-1 pathogenesis in adult and pediatric populations.
Asunto(s)
Infecciones por VIH/virología , VIH-1/aislamiento & purificación , Monocitos/virología , Replicación Viral , Adulto , Niño , Técnicas de Cocultivo , Infecciones por VIH/sangre , VIH-1/fisiología , HumanosRESUMEN
OBJECTIVE: To determine the concentrations of protease inhibitors in cord blood after prenatal protease inhibitor use by pregnant women. DESIGN: Retrospective analysis of samples collected in a clinical trial. METHODS: Protease inhibitor concentrations were measured in cord blood samples collected from women enrolling in the PACTG 316 study who were receiving prenatal protease inhibitor antiretroviral therapy. RESULTS: In cord blood samples from 68 women treated with protease inhibitors during pregnancy, the concentration of these drugs was below the assay lower limit of detection in most samples, including all samples from women receiving indinavir (n = 21) and saquinavir (n = 8), 5 of 6 samples (83%) from women receiving ritonavir and 24 of 38 samples (63%) from women receiving nelfinavir. CONCLUSIONS: Low protease inhibitor concentrations in the fetus decrease the likelihood of teratogenic and toxic effects of these drugs but could fail to provide protection from transplacental or intrapartum transmission of HIV-1.
Asunto(s)
Sangre Fetal/química , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/administración & dosificación , Inhibidores de la Proteasa del VIH/sangre , Intercambio Materno-Fetal , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Adulto , Método Doble Ciego , Femenino , Infecciones por VIH/transmisión , Inhibidores de la Proteasa del VIH/efectos adversos , Inhibidores de la Proteasa del VIH/farmacocinética , Humanos , Recién Nacido , EmbarazoRESUMEN
Recent studies have reported that founder viruses play unique roles in establishing HIV-1 infection. Understanding the biological and immunological features of envelope glycoproteins (Env) from such viruses may facilitate the development of effective vaccines against HIV-1. In this report, we evaluated the immunogenicity of gp120 immunogens from two pairs of clade B and two pairs of clade C mother-to-child transmitted (MTCT) HIV-1 variants that had various levels of sensitivity to broadly neutralizing monoclonal antibodies. Individual gp120 DNA and protein vaccines were produced from each of the eight MTCT Env antigens included in the current study. Rabbits were immunized with these gp120 immunogens by the DNA prime-protein boost approach. High level Env-specific antibody responses were elicited by all MTCT gp120 immunogens. However, their abilities to elicit neutralizing antibody (NAb) responses differed and those from relatively neutralization-resistant variants tended to be more effective in eliciting broader NAb. Results of this pilot study indicated that not all MTCT Env proteins have the same potential to elicit NAb. Understanding the mechanism(s) behind such variation may provide useful information in formulating the next generation of HIV vaccines.