Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 46
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
PLoS One ; 14(11): e0225596, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31756234

RESUMO

HTLV-1 proviral load (pVL) in peripheral blood mononuclear cell (PBMCs) is proposed as a marker of disease progression but its role still remains controversial. The aim of this study was to evaluate the levels of HTLV-1 pVL in symptomatic patients and asymptomatic HTLV-1 carriers. In this cross-sectional study the pVL was measured by Real Time PCR in 102 asymptomatic carriers and 22 symptomatic patients (5ATLL, 15 TSP and 2 uveitis). We observed that the HTLV-1 pVL was significantly higher in symptomatic patients (median = 4.99 log10 HTLV-1 copies /106 PBMCs) compared to asymptomatic HTLV-1 carriers (median = 4.38 log10 HTLV-1 copies /106 PBMCs; p = 0.0030). A wide variation on the HTLV-1 pVL levels among asymptomatic HTLV-1 carriers was observed with some pVL as high as those observed in symptomatic patients. The asymptomatic HTLV-1 carriers were divided according to the place of birth and the highest levels of pVL were detected among patients from endemics areas from the North of Argentina. Our results reinforce the usefulness of the proviral load would be a prognostic marker of HTLV-1 disease progression. Moreover, host, viral or socio-environmental factors cannot be excluded as determinant of high proviral load.

2.
Liver Transpl ; 25(9): 1397-1407, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31102573

RESUMO

Tacrolimus is the cornerstone in pediatric liver transplant immunosuppression. Despite close monitoring, fluctuations in tacrolimus blood levels affect safety and efficacy of immunosuppressive treatments. Identifying the factors related to the variability in tacrolimus exposure may be helpful in tailoring the dose. The aim of the present study was to characterize the clinical, pharmacological, and genetic variables associated with systemic tacrolimus exposure in pediatric liver transplant patients. De novo transplant patients with a survival of more than 1 month were considered for inclusion and were genotyped for cytochrome P450 3A5 (CYP3A5). Peritransplant clinical factors and laboratory covariates were recorded retrospectively between 1 month and 2 years after transplant, including alanine aminotransferase (ALT), aspartate aminotransferase, hematocrit, and tacrolimus predose steady-state blood concentrations collected 12 hours after tacrolimus dosing. A linear mixed effect (LME) model was used to assess the association of these factors and the log-transformed tacrolimus dose-normalized trough concentration (logC0/D) levels. Bootstrapping was used to internally validate the final model. External validation was performed in an independent group of patients who matched the original population. The developed LME model described that logC0/D increases with increases in time after transplant (ß = 0.019, 95% confidence interval [CI], 0.010-0.028) and ALT values (ß = 0.00030, 95% CI, 0.00002-0.00056), whereas logC0/D is significantly lower in graft CYP3A5 expressers compared with nonexpressers (ß = -0.349, 95% CI, -0.631 to -0.062). In conclusion, donor CYP3A5 genotype, time after transplant, and ALT values are associated with tacrolimus disposition between 1 month and 2 years after transplant. A better understanding of tacrolimus exposure is essential to minimize the occurrence of an out-of-range therapeutic window that may lead to adverse drug reactions or acute rejection.

3.
J Antimicrob Chemother ; 74(3): 722-730, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30517632

RESUMO

OBJECTIVES: To assess the prevalence and patterns of pre-treatment HIV drug resistance (PDR) and HIV-1 subtype in infants from Argentina with exposure to different antiretroviral drugs (ARVs) for the prevention of mother-to-child transmission (PMTCT). PATIENTS AND METHODS: HIV-1 genotyping was performed in 115 infants (median age = 2.3 months) born between 2007 and 2014 to screen for drug resistance mutations (DRMs) before starting first-line ART. HIV-1 subtype was characterized by phylogenetic and recombination analysis. RESULTS: Overall, DRMs were found in 34 of 115 infants (PDR level 30% to any ARV, 3.5% to PIs, 12% to NRTIs and 22% to NNRTIs). Of the 115 infants, 22 (19.1%) were ARV-unexposed. Another 93 were ARV-exposed: 28 (24.3%) to short-course zidovudine monotherapy ARV prophylaxis; 25 (21.7%) to nevirapine-based ARV prophylaxis; 12 (10.4%) to perinatal infant zidovudine prophylaxis + maternal combination ART with NNRTIs; and 28 (24.3%) to perinatal infant zidovudine prophylaxis+maternal combination ART with PIs. Transmitted drug resistance among ARV-unexposed infants was 32% (5% to PIs, 9% to NRTIs and 18% to NNRTIs). ART-exposed infants showed multi-class ARV resistance. Importantly, vertical transmission of a triple-class-resistant virus was confirmed in one case. Patterns of DRMs predicted high-level resistance to NNRTIs in a similar and high proportion (>50%) of infants with at least one DRM independently of ARV exposure. BF recombinants were found in 74%, subtype B in 20%, subtype C in 3% and novel AG and AB recombinants in 3%. CONCLUSIONS: PDR in HIV-1-infected children from Argentina is among the highest reported, jeopardizing successful lifelong suppressive ART as well as the efficacy of current PMTCT regimens.

4.
PLoS One ; 13(10): e0205579, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30352067

RESUMO

OBJECTIVE: Determine the decay rate of HIV-1 DNA reservoir in vertically infected children during sustained viral suppression (VS) and how it is affected by the age at VS. METHODS: This study included 37 HIV-1 vertically infected children on suppressive antiretroviral therapy for at least 4 years. Children were grouped according to the age of antiretroviral therapy initiation (≤0.5 or >0.5 yrs) and to the age at VS (≤1.5, between >1.5 and 4, and >4 years). Decay of cell-associated HIV-1 DNA (CA-HIV-DNA) level and 2-long terminal repeats (2-LTR) circles frequency were analyzed over 4 years of viral suppression using piecewise linear mixed-effects model with two splines and logistic regression, respectively. RESULTS: CA-HIV-DNA in peripheral blood mononuclear cells had a significant decay during the first two years of VS [-0.26 (95% CI: -0.43, -0.09) log10 copies per one million cells (cpm)/year], and subsequently reached a plateau [-0.06 (95% CI: -0.15, 0.55) log10 cpm/year]. The initial decay was higher in children who achieved VS by 1.5 years of age compared to those who achieved VS between >1.5 and 4 years and those after 4 years of age: -0.51 (95% CI:-0.94, -0.07), -0.35 (95% CI:-0.83, 0.14), and -0.21 (95% CI:-0.39, -0.02) log10cpm PBMC/year, respectively. The 2-LTR circles frequency decayed significantly, from 82.9% at pre-VS to 37.5% and 28.1% at 2 and 4 years of VS, respectively (P = .0009). CONCLUSIONS: These data highlight that achieving VS during the first 18 months of life limit the establishment of HIV-1 reservoirs, reinforcing the clinical benefit of very early effective therapy in children.


Assuntos
Fármacos Anti-HIV/uso terapêutico , DNA Viral/sangue , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , HIV-1 , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Infecções por HIV/imunologia , HIV-1/genética , Humanos , Lactente , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Estudos Longitudinais , Masculino , Resposta Viral Sustentada , Tempo para o Tratamento , Viremia/sangue , Viremia/tratamento farmacológico , Viremia/imunologia
5.
Respirology ; 20(6): 982-6, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25939617

RESUMO

BACKGROUND AND OBJECTIVE: Post-infectious bronchiolitis obliterans (PIBO) is a severe disorder following acute lower pulmonary infection in young children, especially caused by adenovirus. Mannose-binding lectin (MBL) deficiency arising from polymorphisms in the coding and non-coding region on the MBL2 gene has been associated with more frequent and severe respiratory infections. Our aim was to evaluate the influence of MBL variants in the susceptibility and evolution of children with PIBO. METHODS: One hundred eleven children with PIBO diagnosis were studied. The coding A, B, D and X promoter variants of MBL2 gene were assessed by PCR-RFLP. B and D alleles were pooled as O. The combined genotypes A/A and YA/O were grouped as sufficient MBL (sMBL), and O/O and XA/O as insufficient MBL (iMBL) groups. To evaluate the frequency of MBL2 polymorphisms in the general population, we studied DNA samples from 127 healthy donors from the blood bank of the hospital (control group). RESULTS: iMBL variants were significantly more frequent in PIBO children compared with controls (21.6% vs 10.2%, P = 0.01). PIBO patients with iMBL required intensive care unit (P = 0.001) and mechanical assistance at the moment of viral injury (P = 0.001) more frequently than those with sMBL. CONCLUSIONS: Insufficiency of MBL was more common in PIBO children than in healthy controls. This genetic condition was significantly associated with more severe initial disease, illustrating the relevance of innate immune defence factors prior to the maturation of the adaptative immune system.


Assuntos
Bronquiolite Obliterante/epidemiologia , Lectina de Ligação a Manose/deficiência , Erros Inatos do Metabolismo/epidemiologia , Adolescente , Argentina/epidemiologia , Bronquiolite Obliterante/etiologia , Criança , Pré-Escolar , Suscetibilidade a Doenças , Feminino , Frequência do Gene , Variação Genética , Genótipo , Humanos , Lactente , Masculino , Lectina de Ligação a Manose/genética , Erros Inatos do Metabolismo/genética , Polimorfismo Genético , Infecções Respiratórias/complicações
6.
AIDS Res Hum Retroviruses ; 31(3): 293-7, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25417788

RESUMO

The predominant circulating HIV-1 strains in South America are subtype B and B/F recombinants with different distributions among countries. However, the emergence of other subtypes is a matter of concern and needs continuous monitoring. We identified three different A/G recombinants in Argentina, two of them in vertically infected children from unlinked mothers and one in an adult female. HIV-1 pol sequences from the children showed novel A/G recombination patterns and no phylogenetic relationship with previously reported South American A/G sequences. The third A/G recombinant was a CRF06_cpx with African origin. The detection of new or unusual subtypes is important to avoid false-negative PCR HIV-1 early diagnosis due to detection failures and for future vaccine development.


Assuntos
Variação Genética , Infecções por HIV/virologia , HIV-1/classificação , HIV-1/genética , Recombinação Genética , Adulto , Argentina/epidemiologia , Criança , Pré-Escolar , Análise por Conglomerados , Feminino , Infecções por HIV/epidemiologia , HIV-1/isolamento & purificação , Humanos , Lactente , Recém-Nascido , Dados de Sequência Molecular , Filogenia , Análise de Sequência de DNA , Produtos do Gene pol do Vírus da Imunodeficiência Humana/genética
7.
J Cyst Fibros ; 14(1): 78-83, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25178872

RESUMO

BACKGROUND: There is a considerable variation in the phenotype and course of the disease in cystic fibrosis (CF) even in patients with the same CFTR genotype, suggesting that other factors are important for prognosis. Mannose-binding lectin (MBL) has been proposed as one of these factors. We therefore investigated the influence of MBL2 gene variants on disease severity, age at acquisition of Pseudomonas aeruginosa, and survival in CF patients. METHODS: MBL2 variants were studied in 106 Argentinean pediatric CF patients carrying two severe CFTR mutations. Clinical phenotype was defined according to the Shwachman score and lung function tests. Age at infection with P. aeruginosa and age at death were also recorded. RESULTS: MBL insufficiency was associated with a 3.5-fold risk of having a severe phenotype (CI 95%: 1.2-10.3, p=0.03). It was also associated with an earlier onset of infection with P. aeruginosa (p=0.035). No statistically significant differences were found in FEV1 and survival. CONCLUSIONS: MBL insufficiency was associated with detrimental progression of the disease. These results together with previous findings suggest that the effect of MBL2 expression may be a major determinant of the severity of the clinical phenotype in patients with CF.


Assuntos
Fibrose Cística/genética , Predisposição Genética para Doença/epidemiologia , Lectina de Ligação a Manose/genética , Polimorfismo Genético , Argentina/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Fibrose Cística/mortalidade , Fibrose Cística/fisiopatologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Progressão da Doença , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Fenótipo , Testes de Função Respiratória , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Taxa de Sobrevida
8.
Pediatr Infect Dis J ; 34(2): 155-61, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24988117

RESUMO

BACKGROUND: Lipoprotein lipase is a key enzyme in lipid metabolism, especially for plasma triglycerides (TGs). Genetic variants have been associated with lipid levels in healthy individuals, cardiovascular disease, obesity and diabetes. Our aim was to evaluate the influence of 3 polymorphisms: Hind III, Pvu II and S447X in plasma TG levels in human immunodeficiency virus-1-infected children under highly active antiretroviral therapy (HAART). METHODS: Fifty-two children diagnosed with human immunodeficiency virus-1 between 2005 and 2009 were retrospectively selected with at least 1 plasma TG level assessment. TG levels were examined before and after 1 year of HAART. Hypertriglyceridemia was defined as TG > 150 mg/dL. Hind III (H+/H-), Pvu II (P+/P-) and S447X (S/X) were determined by polymerase chain reaction and restricted fragment length polymorphism. The Wilcoxon sum-rank test was used to compare median plasma TG among groups. Also, allelic frequencies were estimated for these variants in an Argentinean population. RESULTS: Allelic frequencies for human immunodeficiency virus-1-infected children were: H-, 0.21; P-, 0.53; and X, 0.05 with no significant differences to controls. After 1 year of HAART, median TG levels were significantly lower in P-/P- (98.5 mg/dL) when compared with P+/P+ (180 mg/dL) (P = 0.039). The presence of the P- allele was associated with an 11-fold lower risk of hypertriglyceridemia. Hind III and S447X were not associated with TG at the selected time points. CONCLUSIONS: Our findings suggest a protective effect of lipoprotein lipase polymorphisms against hypertriglyceridemia in children after 1 year of HAART. These results could endorse a prompt nutritional or pharmacological intervention in patients lacking the P- allele.


Assuntos
Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/tratamento farmacológico , Lipase Lipoproteica/genética , Lipase Lipoproteica/metabolismo , Polimorfismo Genético , Triglicerídeos/sangue , Argentina , Análise Química do Sangue , Pré-Escolar , Feminino , Frequência do Gene , Genótipo , Humanos , Lactente , Masculino , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Estudos Retrospectivos
9.
PLoS One ; 9(11): e113146, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25406087

RESUMO

BACKGROUND: Variants in HIV-coreceptor C-C chemokine receptor type 5 (CCR5) and Human leukocyte antigen (HLA) genes are the most important host genetic factors associated with HIV infection and disease progression. Our aim was to analyze the association of these genetic factors in the presence of clinical symptoms during Primary HIV Infection (PHI) and disease progression within the first year. METHODS: Seventy subjects diagnosed during PHI were studied (55 symptomatic and 15 asymptomatic). Viral load (VL) and CD4 T-cell count were evaluated. HIV progression was defined by presence of B or C events and/or CD4 T-cell counts <350 cell/mm3. CCR5 haplotypes were characterized by polymerase chain reaction and SDM-PCR-RFLP. HLA-I characterization was performed by Sequencing. RESULTS: Symptoms during PHI were significantly associated with lower frequency of CCR5-CF1 (1.8% vs. 26.7%, p = 0.006). Rapid progression was significantly associated with higher frequency of CCR5-CF2 (16.7% vs. 0%, p = 0.024) and HLA-A*11 (16.7% vs. 1.2%, p = 0.003) and lower frequency of HLA-C*3 (2.8% vs. 17.5%, p = 0.035). Higher baseline VL was significantly associated with presence of HLA-A*11, HLA-A*24, and absence of HLA-A*31 and HLA-B*57. Higher 6-month VL was significantly associated with presence of CCR5-HHE, HLA-A*24, HLA-B*53, and absence of HLA-A*31 and CCR5-CF1. Lower baseline CD4 T-cell count was significantly associated with presence of HLA-A*24/*33, HLA-B*53, CCR5-CF2 and absence of HLA-A*01/*23 and CCR5-HHA. Lower 6-month CD4 T-cell count was associated with presence of HLA-A*24 and HLA-B*53, and absence of HLA-A*01 and HLA-B*07/*39. Moreover, lower 12-month CD4 T-cell count was significantly associated with presence of HLA-A*33, HLA-B*14, HLA-C*08, CCR5-CF2, and absence of HLA-B*07 and HLA-C*07. CONCLUSION: Several host factors were significantly associated with disease progression in PHI subjects. Most results agree with previous studies performed in other groups. However, some genetic factor associations are being described for the first time, highlighting the importance of genetic studies at a local level.


Assuntos
Soropositividade para HIV/genética , Antígenos HLA/genética , Fatores Celulares Derivados do Hospedeiro/metabolismo , Receptores CCR5/genética , Argentina , Western Blotting , Contagem de Linfócito CD4 , Progressão da Doença , Haplótipos/genética , Humanos , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Carga Viral
10.
Actual. SIDA. infectol ; 22(83): 5-9, apr.2014. tab
Artigo em Espanhol | LILACS | ID: lil-777904

RESUMO

El abacavir (ABC) es un antirretroviral inhibidor de la transcriptasa reversa del virus HIV-1 que está fuertemente asociado al desarrollo de reacciones de hipersensibilidad en individuos portadores del alelo HLA-B*5701. Objetivos: determinar la prevalencia del alelo HLA-B*5701 en pacientes HIV-1 positivos y en una población control de Argentina. Materiales y métodos: desde enero de 2012 hasta octubre de 2013 se estudiaron 869 pacientes HIV-1 positivos y 63 individuos no infectados con HIV-1. La detección del alelo HLA-B*5701 se realizó mediante un ensayo in house basado en la técnica de PCR en tiempo real, diseñado en nuestro laboratorio y validado según guías internacionales. Resultados: el primero de enero se implementó el estudio farmacogenético para la detección de hipersensibilidad al ABC en los pacientes incluidos en el Programa VIH/sida de la Dirección de SIDA y ETS, y en los niños infectados con HIV-1 del Hospital Garrahan. Para ello se adoptó un protocolo de envío, recepción y procesado de las muestras, con un informe detallado de los resultados. El alelo HLA-B*5701 se detectó en 42 individuos infectados con HIV-1 y en 3 individuos no infectados. Conclusiones: la prevalencia del alejo HLA-B*5701 en la población de pacientes infectados con HIV-1 y la población control fue la misma (4,8%), lo cual sugiere que la presencia de este alelo no influye en la infección por HIV-1. Esta prevalencia fue similar a la reportada para otras poblaciones de origen caucásico...


Assuntos
Humanos , Alelos , Estudos de Casos e Controles , Avaliação de Medicamentos , Fármacos Anti-HIV/farmacologia , HIV-1 , Inibidores da Transcriptase Reversa/farmacologia
11.
AIDS Res Hum Retroviruses ; 29(7): 1056-60, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23458243

RESUMO

Polymorphisms occurring at the p6gag protein of HIV-1 have been previously found to have an impact on viral fitness and antiretroviral (ARV) resistance, mainly on subtype B genomes. We compared p6gag variability in a large group of 165 subtype F gag-pol sequences, with 36 subtype B sequences from the same study source, and identified sites of gag-pol coevolution under ARV selection pressure. Subtype-specific differences in the frequency of point mutations, insertions, and deletions previously associated with ARV resistance were found. Also, in our dataset of subtype F genomes a strong association between mutation P5L in the p1/p6 cleavage region of gag and the nelfinavir (NFV) resistance mutation N88D(PR) was found with no impact on the preference for any of the NFV resistance pathways.


Assuntos
Genes gag , Genes pol , HIV-1/classificação , HIV-1/genética , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética , Sequência de Aminoácidos , Farmacorresistência Viral/genética , Evolução Molecular , Variação Genética , Genoma Viral , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , Humanos , Dados de Sequência Molecular , Mutação , Nelfinavir/farmacologia
12.
Gene ; 522(1): 96-101, 2013 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-23528223

RESUMO

BACKGROUND: Variability in MDR1 and PXR has been associated with differences in drug plasma levels and response to antiretroviral therapy. We investigated whether polymorphisms in MDR1 (T-129C, C1236T and C3435T) and PXR (C63396T) affect lopinavir plasma concentration and the virological or immunological response to HAART in HIV-1-infected children. METHODS: Genotypes were identified in 100 blood donors and 38 HIV-1-infected children. All children received HAART with lopinavir boosted with ritonavir (LPV/r) at the time of LPV plasma level quantification, before (Ctrough) and between 1 and 2h after (Cpost-dose) the administration of the next dose of drug. CD4(+) T-cell counts and plasma viral load were analyzed before and after the initiation of LPV/r. RESULTS: MDR1 1236T, MDR1 3435T and PXR 63396T alleles showed a frequency of ~50% while the MDR1 -129C allele only reached 5%. Children heterozygotes 1236CT showed a significantly lower LPV Cpost-dose than homozygotes 1236TT (median Cpost-dose=3.04 µg/ml and 6.50 µg/ml, respectively; p=0.016). Children heterozygotes 1236CT also had a lower decrease of viral load after 36 weeks of LPV/r exposure compared with homozygotes 1236CC (median viral load changes=-0.50 log 10 copies/ml and -2.08 log 10 copies/ml, respectively; p=0.047). No effect on the immunological response was observed for polymorphisms of MDR1 or PXR. CONCLUSIONS: Our results suggest that the MDR1 C1236T SNP significantly reduces LPV plasma concentration affecting the virological response to HAART. Heterozygotes 1236CT might have an altered level of P-gp expression/activity in enterocytes and CD4(+) T lymphocytes that limits the absorption of LPV leading to an impaired virological suppression.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Inibidores da Protease de HIV/sangue , HIV-1/efeitos dos fármacos , Lopinavir/sangue , Subfamília B de Transportador de Cassetes de Ligação de ATP , Adolescente , Adulto , Terapia Antirretroviral de Alta Atividade/métodos , Linfócitos T CD4-Positivos/metabolismo , Criança , Pré-Escolar , Feminino , Frequência do Gene , Genótipo , Infecções por HIV/sangue , Infecções por HIV/virologia , Inibidores da Protease de HIV/uso terapêutico , Heterozigoto , Homozigoto , Humanos , Lactente , Lopinavir/uso terapêutico , Masculino , Polimorfismo de Nucleotídeo Único , Receptor de Pregnano X , Receptores de Esteroides/genética , Adulto Jovem
13.
J Med Virol ; 84(12): 1844-52, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23080486

RESUMO

The HIV-1 vif gene encodes for an accessory protein that is central for virus replication due mainly to its capacity to counteract the antiviral action of host APOBEC3 restriction factors. In order to evaluate whether HIV-1 vif alterations account for a delayed progression to AIDS in children infected perinatally, the vif genes from a group of 11 patients who exhibited an extremely slow disease progression (slow progressors) were studied by direct sequencing. In addition, the vif genes from a group of 93 children with typical disease progression (typical progressors) were analyzed for comparison. Phylogenetic analysis indicated that sequences from slow progressors did not have a common origin, discarding a shared ancestor of reduced virulence. There were no differences in the diversity between the vif genes from slow and typical progressors. No gross defects showing a clear distinction among sequences from both groups of children were found. However, in the deduced Vif proteins, changes V13I, V55T, and L81M were observed only in sequences from slow progressors. By analyzing sequences stored in databases, these mutations were determined as unusual substitutions occurring at highly conserved Vif sites across different HIV-1 clades, but were observed with an increased frequency in sequences from elite controllers. These mutations were in the Vif regions reported as relevant for protein activity. These findings suggest that the Vif sequences from slow progressors carry unusual substitutions, which may alter the protein function and may contribute to viral attenuation.


Assuntos
Síndrome de Imunodeficiência Adquirida/virologia , Substituição de Aminoácidos , HIV-1/genética , Transmissão Vertical de Doença Infecciosa , Produtos do Gene vif do Vírus da Imunodeficiência Humana/genética , Desaminase APOBEC-3G , Síndrome de Imunodeficiência Adquirida/transmissão , Sequência de Aminoácidos , Criança , Pré-Escolar , Citidina Desaminase/genética , Bases de Dados Genéticas , Progressão da Doença , Feminino , Genes Virais , Variação Genética , Técnicas de Genotipagem , HIV-1/patogenicidade , HIV-1/fisiologia , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Mutação , Filogenia , Estrutura Terciária de Proteína , Fatores de Tempo , Carga Viral , Replicação Viral
14.
PLoS One ; 7(7): e39678, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22848358

RESUMO

Polymorphisms in apolipoprotein genes have shown to be predictors of plasma lipid levels in adult cohorts receiving highly active antiretroviral therapy (HAART). Our objective was to confirm the association between the APOC3 genotype and plasma lipid levels in an HIV-1-infected pediatric cohort exposed to HAART. A total of 130 HIV-1-infected children/adolescents that attended a reference center in Argentina were selected for an 8-year longitudinal study with retrospective data collection. Longitudinal measurements of plasma triglycerides, total cholesterol, HDL-C and LDL-C were analyzed under linear or generalized linear mixed models. The contribution of the APOC3 genotype at sites -482, -455 and 3238 to plasma lipid levels prediction was tested after adjusting for potential confounders. Four major APOC3 haplotypes were observed for sites -482/-455/3238, with estimated frequencies of 0.60 (C/T/C), 0.14 (T/C/C), 0.11 (C/C/C), and 0.11 (T/C/G). The APOC3 genotype showed a significant effect only for the prediction of total cholesterol levels (p<0.0001). However, the magnitude of the differences observed was dependent on the drug combination (p = 0.0007) and the drug exposure duration at the time of the plasma lipid measurement (p = 0.0002). A lower risk of hypercholesterolemia was predicted for double and triple heterozygous individuals, mainly at the first few months after the initiation of Ritonavir-boosted protease inhibitor-based regimens. We report for the first time a significant contribution of the genotype to total cholesterol levels in a pediatric cohort under HAART. The genetic determination of APOC3 might have an impact on a large portion of HIV-1-infected children at the time of choosing the treatment regimens or on the counter-measures against the adverse effects of drugs.


Assuntos
Terapia Antirretroviral de Alta Atividade/efeitos adversos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , HIV-1 , Haplótipos , Hipercolesterolemia/induzido quimicamente , Hipercolesterolemia/genética , Adolescente , Adulto , Apolipoproteína C-III , Criança , Feminino , Infecções por HIV/sangue , Heterozigoto , Humanos , Hipercolesterolemia/sangue , Lipídeos/sangue , Masculino , Estudos Retrospectivos , Adulto Jovem
15.
Med. infant ; 19(2,n.esp): 81-87, jun. 2012. tab, graf
Artigo em Espanhol | LILACS | ID: lil-774311

RESUMO

El objetivo del trabajo fue determinar la participación del coreceptor CCR5 y su ligando CCL3L1 en relación a una de las características del fenotipo del HIV-1, el tropismo viral. Los resultados que obtuvimos así como otras investigaciones que estamos desarrollando tienen implicancias clínicas y terapéuticas en los niños HIV-1 infectados. Para lograr el objetivo hemos evaluado en forma conjunta y combinada los datos que habíamos obtenido a lo largo de casi 15 años en relación a las variantes genéticas del CCR5, en particular la mutación Δ32 y su ligando CCL3L1 en función del número de copias del gen en los niños HIV-1 infectados por transmisión vertical que son asistidos en el Hospital Garrahan, investigando la probable asociación de ellas con el tropismo viral. Hallamos que los niños en primoinfección tienen una proporción considerable de variantes HIV-1 SI que emplean como co-receptor al CXCR4 en lugar del CCR5. Otro hecho relevante fue que la presencia de las variantes SI predominaron en los niños heterocigotas para la variante genética CCR5Δ32. En este último grupo encontramos además que estaba significativamente asociado con un número de copias del CCL3L1 alto (≥2). Probablemente ambos factores participan favoreciendo la reducción en el número de moléculas del co-receptor CCR5 expresadas en la superficie celular facilitado la infección por las variantes X4. Aunque las variantes SI en la etapa crónica alcanzan a un 40% no parecieran asociadas con el genotipo CCR5Δ32 ni con el número de copias del CCL3L1. En resumen, hemos demostrado que las variantes SI X4 T-trópicas del HIV-1 pueden estar presentes en los estadios muy tempranos de la infección viral sugiriendo que puede ser transmisible verticalmente. Además, el genotipo CCR5Δ32 en el contexto de copias altas del CCL3L1 en el niño HIV-1 infectado, contribuyen a un mayor riesgo a ser infectado por variantes SI en primoinfección. Este hecho no pareciera suceder en la etapa crónica de la infección viral.


The aim of the study was to assess the role of co-receptor CCR5 and its ligand CCL3L1 in viral tropism, one of the char-acteristics of the HIV-1 phenotype. The results of this study as well as those found in our other ongoing research have clini-cal and therapeutic consequences for HIV-1 Infected children. For the aim of the study we collected and evaluated the data obtained over a period of almost 15 years on genetic variants of CCR5, specially the 32 mutation and its ligand CCL3L1 (MIP-1 P), in relation to the number of copies of the gene in HIV-1-mother-to-child infected children seen at the pediatric hospital J.P. Garrahan, to investigate a probable association with viral tropism. We found that children with a primary in-fection have a considerable number of HIV-1 SI (syncytium-inducing, i.e. cytopathic) variants that use CXCR4 instead of CCR5 as a co-receptor. Another relevant finding was that SI variants were predominant in children that were homozygous for the genetic CCR5 32 variant. In this latter group we additionally found that this was significantly associated with a high number of CCL3L1 copies ( 2). Both factors may play a favorable role in the decrease of the number of molecules of the CCR5 co-receptor expressed on the cell surface that facilitate infection through X4 variants. Although in the chronic stage SI variants reach 40%, they do not seem to be associated with either the CCR5 32 genotype or the number of CCL3L1 copies. In sum-mary, we have shown that SI X4 T-tropic variants of HIV-1 may be present in very early stages of viral infection suggesting that they may be transmitted from mother to child. In addition, the CCR5 32 genotype in the setting of a high number of CCL3L1 copies in an HIV-1 infected child contribute to a higher risk of being infected by SI variants in primary infection, however, this mechanism does not seem to occur in the chronic stage of viral infection.


Assuntos
Humanos , Masculino , Feminino , Recém-Nascido , Lactente , Pré-Escolar , Criança , HIV-1 , Transmissão Vertical de Doença Infecciosa , Receptores de HIV , Tropismo Viral , Argentina
16.
AIDS Res Hum Retroviruses ; 28(12): 1617-26, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22583022

RESUMO

Among persons infected by HIV-1, the rate of progression to AIDS is multifactorial being affected by host and viral factors, including the HIV-encoded negative factor (Nef). Our aim was to define whether variations in the nef gene as well as its functions may be associated with slower HIV disease course in infected children. The proviral HIV-1 nef gene was cloned, sequenced, and compared in children with contrasting disease course: 10 long-term nonprogressors (LTNP) and six rapid progressor (RP). The CD4 and MHC-I down-modulation ability of nef alleles derived from LTNP and RP children was analyzed. We observed that only one of our 10 LTNP had a protective genetic background, and out of them, 40% had defective nef genes, carrying substitutions at the (AWLEAQ(56-61)) and the (Rxx(22-24)) domains, and that those alleles were unable of down-regulate CD4 and MHC-I. The emergence or presence of Nef L58V substitution was associated with viral attenuation, indicated by a reduction in HIV viral loads, a persistent preservation of CD4(+) T cell counts, and lack of AIDS-related symptoms. Our results demonstrate that HIV-1 perinatally infected children carrying functionally defective nef HIV-1 strains have prolonged asymptomatic phases without therapy, suggesting a relevant role of CD4 and MHC-I down-modulation Nef domains on in vivo HIV-1 pathogenesis and pediatric immunodeficiency outcome.


Assuntos
Variação Genética , Infecções por HIV/virologia , Sobreviventes de Longo Prazo ao HIV , HIV-1/genética , HIV-1/patogenicidade , Produtos do Gene nef do Vírus da Imunodeficiência Humana/genética , Adolescente , Contagem de Linfócito CD4 , Criança , Pré-Escolar , DNA Viral/genética , Regulação para Baixo , Feminino , HIV-1/isolamento & purificação , Antígenos de Histocompatibilidade Classe I/biossíntese , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Provírus/genética , Análise de Sequência de DNA , Virulência
17.
Infect Genet Evol ; 12(2): 443-7, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22266022

RESUMO

The aim of this work is to characterize the full-length intersubtype recombinant structure of the HIV-1 Circulating Recombinant Form CRF17_BF. A single genome of CRF17_BF was originally described in 2001 as being largely similar to CRF12_BF. Since then, more genomes of CRF17_BF have been sequenced but not adequately described in publications. Here we describe CRF17_BF as a genuine CRF, and analyze its recombination pattern based on bootscan analyses, subtype signature patterns, and phylogenetic reconstruction of subtype-delimited segments. We show that CRF17_BF can be distinguished from CRF12_BF in several regions of the genome, including vpu, pol, env and nef. A complete and accurate characterization and description of recombination breakpoints in CRFs is required for a proper surveillance of HIV-1 genotypes, and important for epidemiological purposes.


Assuntos
Genoma Viral , HIV-1/classificação , HIV-1/genética , Vírus Reordenados/classificação , Vírus Reordenados/genética , Ordem dos Genes , Humanos , Filogenia , Recombinação Genética , Análise de Sequência de DNA
18.
AIDS Res Hum Retroviruses ; 28(7): 685-92, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22023092

RESUMO

The aim of the study was to investigate the prevalence and persistence of syncytium-inducing (SI) strains in HIV-1-infected children along time of infection and to evaluate the influence of antiretroviral therapy and host factors on viral tropism. This is a retrospective analysis carried out in 267 HIV-1 vertically infected children from an Argentinean cohort. The viral phenotype was screened in MT-2 cells and coreceptor usage confirmed by the GHOST cell assay. Also, CD4(+) T cell count, viral load, antiretroviral therapy, and human CCR5-Δ32 and CCR2-64I genotypes were analyzed. A high frequency of HIV-1 SI/CXCR4-using variants (22%) was found among children within the first trimester of life, reaching 46% after 10 years of infection. At acute infection, zidovudine prophylaxis did not significantly affect the proportions of SI HIV-1 strains, while their presence was favored by the CCR5(+)/Δ32 genotype. Interestingly, the majority of the early SI strains did not persist over time, probably due to a higher susceptibility to antiretroviral (ARV) treatment or immunologic pressure. At the chronic stage, SI variants emerged even in the presence of HAART reaching 36% at 120 months of infection. Also the HIV-1 SI phenotype was associated with lower CD4(+) T cell counts all along the course of infection. These findings highlight the need to evaluate the presence of SI/CXCR4 variants early at primary infection. This will make it possible to optimize the use of CCR5 inhibitors in children who are apparently carriers of the R5 virus preventing early therapeutic failure due to the reemergence of SI strains from reservoirs.


Assuntos
Proteína gp160 do Envelope de HIV/imunologia , Soropositividade para HIV/diagnóstico , Soropositividade para HIV/transmissão , HIV-1/fisiologia , Transmissão Vertical de Doença Infecciosa , Receptores CCR5/imunologia , Receptores CXCR4/imunologia , Argentina/epidemiologia , Contagem de Linfócito CD4 , Linhagem Celular Transformada , Pré-Escolar , Diagnóstico Precoce , Feminino , Genótipo , Células Gigantes/imunologia , Proteína gp160 do Envelope de HIV/genética , Soropositividade para HIV/genética , Soropositividade para HIV/imunologia , HIV-1/genética , Humanos , Lactente , Recém-Nascido , Masculino , Gravidez , Receptores CCR5/genética , Receptores CXCR4/genética , Estudos Retrospectivos , Carga Viral , Tropismo Viral
19.
AIDS Res Hum Retroviruses ; 28(6): 619-27, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22145963

RESUMO

The APOBEC3 proteins are cytidine deaminases that can introduce G→A mutations in the HIV-1 plus DNA strand. This editing process may inhibit virus replication through lethal mutagenesis (hypermutation), but could also contribute to viral diversification leading to the emergence of escape forms. The HIV-1 Vif protein has the capacity to counteract APOBEC3 factors by recruiting a CUL5-based ubiquitin ligase complex that determines their proteasomal degradation. In this work, we analyzed the APOBEC3-mediated editing in proviral HIV-1 from perinatally infected children (n=93) in order to explore its association with polymorphisms of APOBEC3G and CUL5 genes (APOBEC3G H186R, APOBEC3G C40693T, and CUL5 SNP6), the Vif protein variability, and also the time to AIDS development. To calculate the level of editing, we have developed an index exploiting the properties of a region within the HIV-1 pol gene that includes the central polypurine tract (cPPT). We detected a reduced editing associated with the CUL5 SNP6 minor allele and also with certain Vif variants (mutations at sites 46, 122, and 160), although we found no evidence supporting an impact of APOBEC3 activity on disease progression. Thus, our findings suggest that APOBEC3-mediated editing of HIV-1 could be modulated by host and virus genetic characteristics in the context of pediatric infection.


Assuntos
Síndrome de Imunodeficiência Adquirida/genética , Proteínas Culina/genética , Citidina Desaminase/genética , HIV-1/genética , Polimorfismo Genético , Produtos do Gene vif do Vírus da Imunodeficiência Humana/genética , Desaminase APOBEC-3G , Síndrome de Imunodeficiência Adquirida/epidemiologia , Síndrome de Imunodeficiência Adquirida/imunologia , Adolescente , Argentina/epidemiologia , Criança , Feminino , Variação Genética , HIV-1/imunologia , Humanos , Masculino , Dados de Sequência Molecular , Mutação/genética , Reação em Cadeia da Polimerase , Replicação Viral
20.
Infect Genet Evol ; 11(6): 1256-62, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21571098

RESUMO

The APOBEC3G protein is a restriction factor that can inhibit the replication of HIV-1. The virus has the capacity to counteract this antiviral activity through the expression of the Vif accessory protein, which recruits a CUL5-based ubiquitin ligase complex that determines APOBEC3G proteasomal degradation. In this work we evaluated in a large pediatric cohort (i) whether single nucleotide polymorphisms of APOBEC3G and CUL5 genes (APOBEC3G H186R, APOBEC3G C40693T and CUL5 SNP6) can alter the risk of HIV-1 vertical transmission and/or the rate of progression to AIDS, (ii) the effect of HIV-1 Vif variants on the clinical course of disease, and (iii) whether the patient genotype for the studied polymorphisms could have an impact on Vif characteristics. We found no effect of the studied APOBEC3G or CUL5 genetic variants on vertical transmission or progression to pediatric AIDS. However, we detected an association of certain Vif alterations (a one amino acid insertion at position 61 and the substitutions A62D/N/S and Q136P) with an accelerated AIDS outcome. Additionally, we observed that the APOBEC3G C40693T and CUL5 SNP6 minor alleles were correlated with substitutions in Vif motifs that are involved in the interaction with APOBEC3G and CUL5 proteins, respectively. Our results suggest that Vif alterations may contribute to a rapid AIDS onset and that Vif variability could be influenced by APOBEC3G and CUL5 polymorphisms in children.


Assuntos
Síndrome de Imunodeficiência Adquirida/genética , Proteínas Culina/genética , Citidina Desaminase/genética , HIV-1/genética , Polimorfismo Genético , Produtos do Gene vif do Vírus da Imunodeficiência Humana/genética , Desaminase APOBEC-3G , Síndrome de Imunodeficiência Adquirida/transmissão , Adolescente , Criança , Pré-Escolar , Progressão da Doença , Estudos de Associação Genética , Variação Genética , Humanos , Lactente , Transmissão Vertical de Doença Infecciosa , Estimativa de Kaplan-Meier , Dados de Sequência Molecular , Análise de Sequência de DNA , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA