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1.
J Infect Dis ; 215(6): 928-932, 2017 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-28453843

RESUMEN

Biomarkers of inflammation and immune activation were correlated with rotavirus vaccine responses in 68 human immunodeficiency virus type 1 (HIV-1)­infected (and 116 HIV-exposed but uninfected (HEU) African infants receiving pentavalent rotavirus vaccine (RV5) in a clinical trial. Prevaccination, HIV-1+ infants had significantly higher concentrations of interferon γ (IFNγ), interleukin1ß, interleukin 2, interleukin 6, interleukin 10 (IL-10), and soluble CD14 compared with HEU infants. Postvaccination concentrations of neutralizing antibodies to RV5 were negatively correlated with prevaccination concentrations of IL-10 (RV5 surface proteins G1 and P1) and IFNγ (G1) in the HIV-1+ infants, whereas antirotavirus immunoglobulin A (IgA) levels were not. Heightened inflammation and immune activation in HIV-1+ infants did not alter IgA responses associated with protection from rotavirus disease.


Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Infecciones por Rotavirus/prevención & control , Vacunas contra Rotavirus/uso terapéutico , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Terapia Antirretroviral Altamente Activa , Biomarcadores/sangre , Botswana , Recuento de Linfocito CD4 , Citocinas/sangre , Método Doble Ciego , Femenino , VIH-1/inmunología , Humanos , Inmunoglobulina A/sangre , Lactante , Inflamación , Masculino , Análisis Multivariante , Tanzanía , Zambia , Zimbabwe
2.
Clin Infect Dis ; 64(11): 1471-1478, 2017 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-28329153

RESUMEN

BACKGROUND.: Early antiretroviral therapy (ART) limits proviral reservoirs, a goal for human immunodeficiency virus type 1 (HIV-1) remission strategies. Whether this is an immediate or long-term effect of virologic suppression (VS) in perinatal infection is unknown. METHODS.: We quantified HIV-1 DNA longitudinally for up to 14 years in peripheral blood mononuclear cells (PBMCs) among 61 perinatally HIV-1-infected youths in the Pediatric HIV/AIDS Cohort Study who achieved VS at different ages. Participants in group 1 (n = 13) were <1 year of age and in group 2 (n = 48) from 1 through 5 years of age at VS. Piecewise linear mixed-effects regression models assessed the effect of age at VS on HIV-1 DNA trajectories during VS. RESULTS.: In the first 2 years following VS, HIV-1 DNA levels decreased by -0.25 (95% confidence interval [CI], -.36 to -.13) log10 copies/million PBMCs per year and was faster with early VS by age 1 year compared with after age 1 (-0.50 and -0.15 log10 copies/million PBMCs per year, respectively). Between years 2 and 14 from VS, HIV-1 DNA decayed by -0.05 (95% CI, -.06 to -.03) log10 copies/million PBMCs per year and was no longer significantly different between groups. The estimated mean half-life of HIV-1 DNA from VS was 15.9 years and was shorter for group 1 compared to group 2 at 5.9 years and 18.8 years, respectively (P = .09). Adjusting for CD4 cell counts had no effect on decay estimates. CONCLUSIONS.: Early effective, long-term ART initiated from infancy leads to decay of HIV-1-infected cells to exceedingly low concentrations desired for HIV-1 remission strategies.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , ADN Viral/metabolismo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Leucocitos Mononucleares/virología , Adolescente , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Preescolar , Estudios de Cohortes , ADN Viral/sangre , Femenino , Estudios de Seguimiento , Infecciones por VIH/prevención & control , VIH-1/genética , Humanos , Lactante , Recién Nacido , Leucocitos Mononucleares/efectos de los fármacos , Modelos Lineales , Estudios Longitudinales , Masculino , Provirus/genética , Carga Viral/efectos de los fármacos
3.
N Engl J Med ; 369(19): 1828-35, 2013 Nov 07.
Artículo en Inglés | MEDLINE | ID: mdl-24152233

RESUMEN

An infant born to a woman with human immunodeficiency virus type 1 (HIV-1) infection began receiving antiretroviral therapy (ART) 30 hours after birth owing to high-risk exposure. ART was continued when detection of HIV-1 DNA and RNA on repeat testing met the standard diagnostic criteria for infection. After therapy was discontinued (when the child was 18 months of age), levels of plasma HIV-1 RNA, proviral DNA in peripheral-blood mononuclear cells, and HIV-1 antibodies, as assessed by means of clinical assays, remained undetectable in the child through 30 months of age. This case suggests that very early ART in infants may alter the establishment and long-term persistence of HIV-1 infection.


Asunto(s)
Antirretrovirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1 , ARN Viral/sangre , Viremia , Preescolar , Anticuerpos Anti-VIH/sangre , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/genética , VIH-1/aislamiento & purificación , Humanos , Masculino , Carga Viral , Viremia/diagnóstico , Privación de Tratamiento
4.
Clin Infect Dis ; 61(12): 1862-70, 2015 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-26270687

RESUMEN

BACKGROUND: The decay of human immunodeficiency virus type 1 (HIV-1)-infected cells during early combination antiretroviral therapy (cART) in infected infants is not defined. METHODS: HIV-1 DNA, including 2-long terminal repeat (2-LTR) circles, and multiply spliced (ms-) and unspliced (us-) HIV-1 RNA concentrations were measured at 0, 24, 48, and 96 weeks of cART in infants from the IMPAACT P1030 trial receiving lopinavir-ritonavir-based cART. The ratio of HIV-1 DNA concentrations to replication-competent genomes was also estimated. Linear mixed effects models with random intercept and linear splines were used to estimate patient-specific decay kinetics of HIV-1 DNA. RESULTS: The median HIV-1 DNA concentration before cART at a median age of 2 months was 3.2 log10 copies per million PBMC. With cART, the average estimated patient-specific change in HIV-1 DNA concentrations was -0.040 log10/week (95% confidence interval [CI], -.05, -.03) between 0 and 24 weeks and -0.017 log10/week between 24 and 48 weeks (95% CI, -.024, -.01). 2-LTR circles decreased with cART but remained detectable through 96 weeks. Pre-cART HIV-1 DNA concentration was correlated with time to undetectable plasma viral load and post-cART HIV-1 DNA at 96 weeks; although HIV-1 DNA concentrations exceeded replication-competent HIV-1 genomes by 148-fold. Almost all infants had ms- and usRNA detected pre-cART, with 75% having usRNA through 96 weeks of cART. CONCLUSIONS: By 2 months of age, a large pool of HIV-1-infected cells is established in perinatal infection, which influences time to undetectable viral load and reservoir size. This has implications for informing novel approaches aimed at early restriction of HIV-1 reservoirs to enable virologic remission and cure.


Asunto(s)
Antirretrovirales/administración & dosificación , ADN Viral/análisis , Infecciones por VIH/tratamiento farmacológico , VIH-1/aislamiento & purificación , Leucocitos Mononucleares/virología , ARN Viral/análisis , Prevención Secundaria , Terapia Antirretroviral Altamente Activa/métodos , Femenino , Infecciones por VIH/virología , VIH-1/genética , Humanos , Lactante , Recién Nacido , Masculino , Estabilidad del ARN , Carga Viral
5.
J Infect Dis ; 210(10): 1529-38, 2014 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-24850788

RESUMEN

BACKGROUND: Early initiation of combination antiretroviral therapy (cART) to human immunodeficiency virus type 1 (HIV-1)-infected infants controls HIV-1 replication and reduces mortality. METHODS: Plasma viremia (lower limit of detection, <2 copies/mL), T-cell activation, HIV-1-specific immune responses, and the persistence of cells carrying replication-competent virus were quantified during long-term effective combination antiretroviral therapy (cART) in 4 perinatally HIV-1-infected youth who received treatment early (the ET group) and 4 who received treatment late (the LT group). Decay in peripheral blood mononuclear cell (PBMC) proviral DNA levels was also measured over time in the ET youth. RESULTS: Plasma viremia was not detected in any ET youth but was detected in all LT youth (median, 8 copies/mL; P = .03). PBMC proviral load was significantly lower in ET youth (median, 7 copies per million PBMCs) than in LT youth (median, 181 copies; P = .03). Replication-competent virus was recovered from all LT youth but only 1 ET youth. Decay in proviral DNA was noted in all 4 ET youth in association with limited T-cell activation and with absent to minimal HIV-1-specific immune responses. CONCLUSIONS: Initiation of early effective cART during infancy significantly limits circulating levels of proviral and replication-competent HIV-1 and promotes continuous decay of viral reservoirs. Continued cART with reduction in HIV-1 reservoirs over time may facilitate HIV-1 eradication strategies.


Asunto(s)
Antirretrovirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/aislamiento & purificación , Provirus/aislamiento & purificación , Prevención Secundaria , Carga Viral , Adolescente , Terapia Antirretroviral Altamente Activa/métodos , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Lactante , Recién Nacido , Leucocitos Mononucleares/virología , Masculino , Resultado del Tratamiento
6.
J Infect Dis ; 207(12): 1829-40, 2013 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-23482645

RESUMEN

BACKGROUND: The licensing of herpes zoster vaccine has demonstrated that therapeutic vaccination can help control chronic viral infection. Unfortunately, human trials of immunodeficiency virus (HIV) vaccine have shown only marginal efficacy. METHODS: In this double-blind study, 17 HIV-infected individuals with viral loads of <50 copies/mL and CD4(+) T-cell counts of >350 cells/µL were randomly assigned to the vaccine or placebo arm. Vaccine recipients received 3 intramuscular injections of HIV DNA (4 mg) coding for clade B Gag, Pol, and Nef and clade A, B, and C Env, followed by a replication-deficient adenovirus type 5 boost (10(10) particle units) encoding all DNA vaccine antigens except Nef. Humoral, total T-cell, and CD8(+) cytotoxic T-lymphocyte (CTL) responses were studied before and after vaccination. Single-copy viral loads and frequencies of latently infected CD4(+) T cells were determined. RESULTS: Vaccination was safe and well tolerated. Significantly stronger HIV-specific T-cell responses against Gag, Pol, and Env, with increased polyfunctionality and a broadened epitope-specific CTL repertoire, were observed after vaccination. No changes in single-copy viral load or the frequency of latent infection were observed. CONCLUSIONS: Vaccination of individuals with existing HIV-specific immunity improved the magnitude, breadth, and polyfunctionality of HIV-specific memory T-cell responses but did not impact markers of viral control. CLINICAL TRIALS REGISTRATION: NCT00270465.


Asunto(s)
Vacunas contra el SIDA/inmunología , Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/inmunología , VIH/inmunología , Subgrupos de Linfocitos T/inmunología , Adulto , Secuencia de Aminoácidos , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Linfocitos T CD8-positivos/inmunología , Método Doble Ciego , Mapeo Epitopo , Epítopos de Linfocito T/inmunología , Estudios de Seguimiento , Infecciones por VIH/terapia , Infecciones por VIH/virología , Humanos , Inmunidad Humoral , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Proteínas Recombinantes , Linfocitos T Citotóxicos/inmunología , Vacunación , Carga Viral , Latencia del Virus
8.
J Clin Microbiol ; 49(12): 4077-82, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21956987

RESUMEN

Monitoring HIV drug resistance is an important component of the World Health Organization's global HIV program. HIV drug resistance testing is optimal with commercially available clinically validated test kits using plasma; however, that type of testing may not be feasible or affordable in resource-constrained settings. HIV genotyping from dried blood spots (DBS) with noncommercial (in-house) assays may facilitate the capture of HIV drug resistance outcomes in resource-constrained settings but has had varying rates of success. With in-house assays for HIV reverse transcriptase, we evaluated the yield of genotyping DBS samples collected from HIV-infected children who were enrolled in two clinical trials conducted in sub-Saharan Africa (median HIV viral load, 5.88 log(10) HIV RNA copies/ml; range, 4.04 to 6.99). Overall, HIV genotypes were obtained for 94 (89.5%) of 105 samples tested (95% and 84% from clinical trials #1 and #2, respectively); however, successful analysis of 15 (16.1%) of the 94 samples required repeat testing using a different set of primers on previously synthesized cDNA. The yield of genotyping was lower on the DBS that were stored suboptimally from clinical trial #2 (56% versus 88% for optimally stored). Concordance with plasma genotypes derived using a clinically validated, commercial kit-based assay (ViroSeq HIV-1 genotyping system) was also assessed in a subset of children with paired testing. For 34 samples with paired DBS and plasma genotypes, there was 100% concordance for major drug resistance mutations. DBS genotyping using in-house assays provides an alternative for antiretroviral drug resistance testing in children in resource-constrained regions but may require region-specific optimization before widespread use.


Asunto(s)
Sangre/virología , Desecación , Farmacorresistencia Viral , Infecciones por VIH/diagnóstico , Infecciones por VIH/virología , VIH-1/genética , Manejo de Especímenes/métodos , África del Sur del Sahara , Antirretrovirales/farmacología , Niño , Preescolar , Países en Desarrollo , Genotipo , Transcriptasa Inversa del VIH/genética , VIH-1/aislamiento & purificación , Humanos , Lactante
9.
J Virol ; 83(19): 9731-42, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19605490

RESUMEN

In most human immunodeficiency virus type 1 (HIV-1)-infected individuals who achieve viral loads of <50 copies/ml during highly active antiretroviral therapy (HAART), low levels of plasma virus remain detectable for years by ultrasensitive methods. The relative contributions of ongoing virus replication and virus production from HIV-1 reservoirs to persistent low-level viremia during HAART remain controversial. HIV-1 vaccination of HAART-treated individuals provides a model for examining low-level viremia, as immunizations may facilitate virus replication and sequence evolution. In a phase 1 trial of modified vaccinia virus Ankara/fowlpox virus-based HIV-1 vaccines in 20 HIV-infected young adults receiving HAART, we assessed the prevalence of low-level viremia and sequence evolution, using ultrasensitive viral load (<6.5 copies/ml) and genotyping (five-copy sensitivity) assays. Viral evolution, consisting of new drug resistance mutations and novel amino acid changes within a relevant HLA-restricted allele (e.g., methionine, isoleucine, glutamine, or arginine for leucine at position 205 of RT), was found in 1 and 3 of 20 subjects, respectively. Sequence evolution was significantly correlated with levels of viremia of between 6.5 and <50 copies/ml (P = 0.03) and was more likely to occur within epitopes presented by relevant HLA alleles (P < 0.001). These findings suggest that ongoing virus replication contributes to low-level viremia in patients on HAART and that this ongoing replication is subject to CD8(+) T-cell selective pressures.


Asunto(s)
Antirretrovirales/farmacología , Infecciones por VIH/virología , VIH-1/metabolismo , Poxviridae/genética , Adulto , Terapia Antirretroviral Altamente Activa , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/virología , Estudios de Cohortes , Femenino , Genotipo , Infecciones por VIH/tratamiento farmacológico , Humanos , Inmunización , Masculino , Análisis de Secuencia de ADN
10.
AIDS ; 33(2): 211-218, 2019 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-30325763

RESUMEN

OBJECTIVE: Timely initiation of combination antiretroviral therapy (ART) limits latent HIV reservoir size and should also limit reservoir genetic complexity. However, the relationship between these two factors remains unclear, particularly among HIV-infected youth. DESIGN: Retrospective analysis of replication-competent latent HIV clones serially isolated by limiting-dilution culture from resting CD4 T-cell reservoirs from ART-suppressed, young adult participants of a historic phase I therapeutic vaccine trial (PACTG/IMPAACT-P1059). METHODS: Replication-competent latent HIV clones isolated from resting CD4 T cells of four perinatally and 10 nonperinatally infected young adults (average 22 versus 6 years uncontrolled infection, respectively) were sequenced in Pol and Nef. Within-host HIV sequence datasets were characterized with respect to their genetic diversity and inferred immune escape mutation burden. RESULTS: Although participants were comparable in terms of sociodemographic and HIV sampling characteristics (e.g. on average, a mean 17 Pol sequences were recovered at five timepoints over up to 70 weeks) and the length of ART suppression at study entry (average 3 years), replication-competent HIV reservoir size, genetic diversity, immune escape mutation burden and variant complexity were significantly higher among the perinatally infected participants who experienced longer durations of uncontrolled viremia. Nevertheless, viral sequences inferred to retain susceptibility to host cellular immune responses were detected in all participants, irrespective of uncontrolled viremia duration. CONCLUSION: HIV elimination in late-suppressed youth may be doubly challenged by larger and more genetically complex reservoirs. Strategies that integrate host and viral genetic complexity to achieve HIV remission or cure may merit consideration in such cases.


Asunto(s)
Antirretrovirales/uso terapéutico , Variación Genética , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH/clasificación , VIH/genética , Latencia del Virus , Adolescente , Linfocitos T CD4-Positivos/virología , ADN Viral/química , ADN Viral/genética , Femenino , Humanos , Masculino , Estudios Retrospectivos , Análisis de Secuencia de ADN , Adulto Joven , Productos del Gen nef del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen pol del Virus de la Inmunodeficiencia Humana/genética
11.
Pediatr Infect Dis J ; 37(12): e298-e303, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-29746376

RESUMEN

BACKGROUND: HIV is a neuropathogenic virus that may result in detrimental neurodevelopmental (ND) outcomes early in life. This is the first study to evaluate the effect of HIV-1 subtype on neurodevelopment of Ugandan preschool children. METHODS: Neurodevelopment of 87 HIV-1 infected and 221 HIV exposed uninfected Ugandan children 1.8-4.9 years of age was assessed using 4 scales of the Mullen Scales of Early Learning (MSEL), 2 scales of the Color Object Association Test (COAT), and 1 score of the Early Childhood Vigilance Test. HIV-1 subtype was defined by phylogenetic analyses. General linear models were used to relate test scores to HIV-1 subtype (A versus D) while adjusting for relevant covariates. The scores were benchmarked against HIV exposed uninfected group to facilitate the interpretation. RESULTS: Seventy-one percentage of children infected with subtype A versus 60% of children with subtype D were currently on antiretroviral therapy (P = 0.49). Children with HIV-1 subtype A infection were older when compared with subtype D (3.29 vs. 2.76 years, respectively, P = 0.03), but similar regarding sex, socioeconomic status, weight-for-age z-score, CD4+ and CD8+ (% and total), viral load. No statistically significant differences by HIV-1 subtype were observed in the MSEL, COAT and Early Childhood Vigilance Test. Differences ≥ 0.33 of the SD were observed for the MSEL Composite Score, Receptive Language (MSEL) and Total Memory (COAT). CONCLUSIONS: In contrast to previously reported differences in ND outcomes of school-age children by HIV-1 subtype, ND scores among preschool children were similar for subtypes A and D, with few potential differences on language production and memory outcomes that favored subtype A. Further investigation with larger sample sizes and longitudinal follow-up is needed.


Asunto(s)
Desarrollo Infantil , Infecciones por VIH/complicaciones , Trastornos del Neurodesarrollo/epidemiología , Preescolar , Estudios Transversales , Femenino , VIH-1 , Humanos , Lactante , Masculino , Trastornos del Neurodesarrollo/virología , Examen Neurológico/métodos , Uganda/epidemiología
12.
AIDS Res Hum Retroviruses ; 23(3): 381-90, 2007 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17411371

RESUMEN

A longitudinal study of viral reservoirs in children initiating highly active antiretroviral therapy (HAART) in early infancy was undertaken to test the hypothesis that early effective treatment affects the persistence of replication-competent viral latency and the evolution of HIV-1 in resting CD4(+) T cells. An end point dilution culture assay was used to measure the frequencies of latently-infected resting CD4(+) T cells harboring replication-competent virus in early and late treated children. Gag, pol, and env also were sequenced and compared to pretreatment sequences. HIV-1-specific humoral and cellular immune responses were also assessed. Blood samples were obtained from 12 HIV-1-infected children who started HAART at a median of 1.9 months of age and who maintained suppression of HIV-1 replication for up to 5.5 years. Replication-competent HIV-1 was recovered from 10/12 (84%) subjects. Evolution in gag, pol, and env was restricted for years in early-treated children. HAART initiated from early infancy does not prevent the establishment of a reservoir of latent provirus, but does significantly limit the evolution of HIV-1 in viral reservoirs. The effect of early therapy on HIV-1 evolution may have implications for long-term pharmacologic control of HIV-1.


Asunto(s)
Terapia Antirretroviral Altamente Activa , Linfocitos T CD4-Positivos/virología , Evolución Molecular , Infecciones por VIH/tratamiento farmacológico , VIH-1/fisiología , Latencia del Virus/fisiología , Replicación Viral/fisiología , Preescolar , Esquema de Medicación , Genes env/genética , Genes pol/genética , VIH-1/efectos de los fármacos , VIH-1/genética , Humanos , Lactante , Recién Nacido , Estudios Longitudinales , Filogenia , ARN Viral/sangre , Carga Viral , Latencia del Virus/genética
13.
PLoS One ; 12(2): e0170548, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28178277

RESUMEN

The latent reservoir is a major barrier to HIV eradication. Reservoir size is emerging as an important biomarker to assess the likelihood of HIV remission in the absence of antiretroviral therapy (ART) and may be reduced by earlier initiation of ART that restricts HIV spread into CD4+ T cells. Reservoir size is traditionally measured with a quantitative viral outgrowth assay (QVOA) that induces replication-competent HIV production through in vitro stimulation of resting CD4+ T cells. However, the recent identification of replication-intact, non-induced proviral genomes (NIPG) suggests the QVOA significantly underestimates (by 62-fold) latent reservoir size in chronically-infected adults. Whether formation and persistence of Intact, NIPG is thwarted by early ART initiation and long-term virologic suppression in perinatal infection is unclear. Here, we show that the latent reservoir in 11 early treated, long-term suppressed perinatally infected children and adolescents was not inducible by QVOA and dominated by defective, NIPG. Single genome analysis of 164 NIPG from 232 million cultured resting CD4+ T cells revealed no replication-intact, near-full length sequences. Forty-three (26%) NIPG contained APOBEC3G-mediated hypermutation, 115 (70%) NIPG contained large internal deletions, one NIPG contained nonsense mutations and indels, and 5 (3%) NIPG were assigned as "Not Evaluable" due to multiple failed sequencing attempts that precluded further classification. The lack of replication competent inducible provirus and intact NIPG in this cohort indicate early, long-term ART of perinatal infection leads to marked diminution of replication-competent HIV-1 reservoirs, creating a favorable state towards interventions aimed at virologic remission.


Asunto(s)
Infecciones por VIH/virología , VIH-1/fisiología , Complicaciones Infecciosas del Embarazo , Provirus , Adolescente , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Niño , Preescolar , ADN Viral , Femenino , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Humanos , Lactante , Mutación , Embarazo , Provirus/genética , Carga Viral , Latencia del Virus
14.
J Virol Methods ; 136(1-2): 238-47, 2006 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16828172

RESUMEN

Exposure to antiretroviral drugs in resource-constrained settings is likely to result in the emergence of drug-resistant HIV-1 variants, limiting treatment options. Genotypic drug resistance testing assists clinical management and outcomes assessment, but a sensitive and reproducible genotypic assay feasible for resource-constrained settings is needed. A sensitive, reproducible genotyping assay to detect HIV-1 drug resistance mutations in reverse transcriptase and protease was developed and validated using blood stored as dried blood spots or as frozen RNA extracts from Zambian children infected with subtype C. HIV-1 genotypes derived from samples stored as dried blood spots were compared to those derived from paired liquid plasma samples in American young adults infected with HIV-1 subtype B. The method reproducibly amplified patient-specific sequences and detected drug resistance mutations from all of the dried blood spots or excess frozen RNA extracts with detectable viremia over a broad range of viral loads (193-3 million HIV-1 RNA copies/mL) in both HIV-1 subtypes B and C infection. This method captured the genetic variation typical of HIV-1 infection, including mutations at usual sites of drug resistance, polymorphisms, and mixtures. This sensitive and reproducible genotypic assay is feasible for detection of antiretroviral resistance in resource-constrained settings.


Asunto(s)
Farmacorresistencia Viral/genética , Transcriptasa Inversa del VIH/genética , VIH-1/efectos de los fármacos , VIH-1/genética , Mutación , Adolescente , Adulto , Secuencia de Aminoácidos , Niño , Femenino , Genoma Viral , Genotipo , Proteasa del VIH , Humanos , Lactante , Masculino , Datos de Secuencia Molecular , ARN Viral/genética , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Zambia
15.
AIDS ; 29(15): 1953-61, 2015 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-26153671

RESUMEN

OBJECTIVE: The objective of this study is to determine whether detection of HIV infection was delayed in infants exposed to antiretroviral prophylaxis to prevent HIV transmission during breastfeeding. DESIGN: The Breastfeeding, Antiretrovirals and Nutrition (BAN) study was a randomized trial of 2369 mother-infant pairs conducted from 2004 to 2010. In addition to an intrapartum regimen, all mother-infant pairs were randomly assigned to three antiretroviral intervention arms during 28 weeks of breastfeeding: no further antiretroviral prophylaxis (control arm); infant-daily nevirapine (nevirapine arm); and maternal zidovudine, lamivudine and either nevirapine, nelfinavir or lopinavir-ritonavir (maternal arm). After breastfeeding cessation counselling and stopping the antiretroviral interventions by 28 weeks, 28 infant HIV infections occurred. METHODS: To determine whether these infections occurred during the breastfeeding and antiretroviral intervention phase but had delayed detection on the antiretroviral arms, we performed ultrasensitive (droplet digital PCR) HIV testing on infants with stored peripheral blood mononuclear cell (PBMC) specimens at 24 weeks (n = 9). RESULTS: Of the nine infants, all three on the infant nevirapine arm had detectable HIV DNA at 24 weeks, compared with two of four on the maternal antiretroviral arm and one of two on the control arm. For infants with detectable HIV at 24 weeks, the median delay in detection between the ultrasensitive and standard assays was 18.3 weeks for the nevirapine arm, 15.4 weeks for the maternal arm and 9.4 weeks for the control arm. CONCLUSION: The prolonged inability to detect HIV with standard assays in the context of postnatal antiretroviral prophylaxis suggests that early antiretrovirals may restrict HIV replication sufficiently to lead to missed diagnosis among infected infants. Therefore, repeat virologic testing is warranted beyond the WHO-recommended point of testing at 6 weeks after breastfeeding cessation.


Asunto(s)
Antirretrovirales/administración & dosificación , Lactancia Materna , Diagnóstico Tardío , Infecciones por VIH/diagnóstico , Infecciones por VIH/transmisión , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Pruebas Diagnósticas de Rutina/métodos , Técnicas de Genotipaje , VIH/clasificación , VIH/genética , VIH/aislamiento & purificación , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Humanos , Lactante , Recién Nacido , Epidemiología Molecular
16.
JAMA Pediatr ; 168(12): 1138-46, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25286283

RESUMEN

IMPORTANCE: Combination antiretroviral therapy initiated within several weeks of human immunodeficiency virus (HIV) infection in adults limits proviral reservoirs that preclude HIV cure. Biomarkers of restricted proviral reservoirs may aid in the monitoring of HIV remission or cure. OBJECTIVES: To quantify peripheral blood proviral reservoir size in perinatally HIV-infected (PHIV+) adolescents and to identify correlates of limited proviral reservoirs. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study including 144 PHIV+ youths (median age, 14.3 years) enrolled in the United States-based Pediatric HIV/AIDS Cohort Study and receiving durable (median duration, 10.2 years) combination antiretroviral therapy, stratified by age at virologic control. MAIN OUTCOMES AND MEASURES: The primary end point was peripheral blood mononuclear cell (PBMC) proviral load after virologic control at different ages. Correlations between proviral load and markers of active HIV production (ie, HIV-specific antibodies, 2-long terminal repeat circles) and markers of immune activation and inflammation were also assessed. RESULTS: Proviral reservoir size was markedly reduced in the PHIV+ youth who achieved virologic control before 1 year of age (4.2 [interquartile range, 2.6-8.6] copies per 1 million PBMCs) compared with those who achieved virologic control at 1 to 5 years of age (19.4 [interquartile range, 5.5-99.8] copies per 1 million PBMCs) or after 5 years of age (70.7 [interquartile range, 23.2-209.4] copies per 1 million PBMCs; P < .001). A proviral burden of less than 10 copies per 1 million PBMCs in PHIV+ youth was measured in 11 (79%), 20 (40%), and 13 (18%) participants with virologic control before 1 year, at 1 to 5 years, and after 5 years of age, respectively (P < .001). Lower proviral load was associated with undetectable 2-long terminal repeat circles (P < .001) and HIV-negative or indeterminate serostatus (P < .001) but not with concentrations of soluble immune activation markers CD14 and CD163. CONCLUSIONS AND RELEVANCE: Early effective combination antiretroviral therapy with prolonged virologic suppression after perinatal HIV infection leads to negligible peripheral blood proviral reservoirs in adolescence and is associated with negative or indeterminate HIV serostatus. These findings highlight the long-term effect of early effective control of HIV replication on biomarkers of HIV persistence in perinatal infection and the utility of HIV serostatus as a biomarker for small proviral reservoir size, although not necessarily for cure.


Asunto(s)
Antirretrovirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Leucocitos Mononucleares/virología , Provirus , Carga Viral , Adolescente , Factores de Edad , Recuento de Linfocito CD4 , Niño , Preescolar , Estudios Transversales , Femenino , Infecciones por VIH/transmisión , Humanos , Lactante , Transmisión Vertical de Enfermedad Infecciosa , Masculino , Factores de Riesgo , Resultado del Tratamiento , Estados Unidos
17.
AIDS ; 26(12): 1483-90, 2012 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-22555165

RESUMEN

OBJECTIVES: Identification of HIV infection in exposed infants facilitates early therapy, which may limit viral reservoirs that maintain HIV infection under HAART. METHODS: The dynamics of the resting CD4 T-cell latent HIV reservoir was determined over the first 2 years of life in 17 HIV-infected infants initiating lopinavir/ritonavir-based HAART at a median age of 8.1 weeks and achieving adequate suppression of plasma viral load by 24 weeks. RESULTS: The resting CD4 T-cell latent HIV reservoir was detected in 12 of 14 (86%) infants tested at 24 weeks of HAART [median frequency 1.88 infectious units per million (IUPM); range <0.22 to 81.7), and remained measurable (median IUPM = 0.32; range <0.22 to 3.25) in six of 10 (60%) children retested at 96 weeks. The reservoir declined, from 24 to 96 weeks of HAART, at an estimated mean rate of 0.028 log10 IUPM/month, corresponding to a half-life of 11 months (95% confidence interval 6-30 months]. A strong relationship was found between the frequency of latently infected CD4 T cells at 96 weeks of HAART and time to first undetectable plasma viral load (Spearman r = 0.91, P < 0.001). CONCLUSION: Although the resting CD4 T-cell latent reservoir remains detectable over the first 2 years of HAART in a substantial proportion of infants, its size is associated with time to first undetectable viral load. To minimize HIV reservoirs in infants, rapid curtailment of viremia may limit HIV reservoirs and should be a therapeutic goal of early HAART in infants.


Asunto(s)
Linfocitos T CD4-Positivos/virología , Reservorios de Enfermedades/virología , Infecciones por VIH/virología , Terapia Antirretroviral Altamente Activa , Femenino , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/administración & dosificación , VIH-1/fisiología , Humanos , Lactante , Lopinavir/administración & dosificación , Masculino , Ritonavir/administración & dosificación , Resultado del Tratamiento , Carga Viral , Latencia del Virus , Replicación Viral
18.
AIDS ; 25(18): 2227-34, 2011 Nov 28.
Artículo en Inglés | MEDLINE | ID: mdl-21918423

RESUMEN

OBJECTIVES: Therapeutic HIV vaccinations may alter the size of the resting memory CD4 T-cell latent HIV reservoir as HIV establishes latency when memory responses are formed, including those toward HIV. Alternatively, latently infected CD4 T cells maybe killed, while exiting the reservoir upon activation. METHODS: The effect of therapeutic immunization with modified vaccinia Ankara and Fowlpox-based HIV vaccines on the latent reservoir was examined in 19 young adults who were receiving effective antiretroviral therapy. Correlations between size of the reservoir [measured in infectious units per million (IUPM)] resting CD4 T cells and HIV-specific immune responses, including immune activation were examined. Decay of the reservoir was assessed using random-effects model. RESULTS: A modest transient decrease in the size of the reservoir was observed at week 40 [mean -0.31 log(10) IUPM (95% confidence interval: -0.60 to -0.03; P = 0.03] following HIV vaccinations. The estimated half-life (T1/2) of the reservoir during the 40 weeks following vaccination was 9.8 months and statistically different from zero (P = 0.02), but 35.3 months and not different from zero (P = 0.21) over 72 weeks of study. Latent reservoir size at baseline was not correlated with HIV-specific CD4, CD8 responses or immune activation, but became correlated with CD4 IFNγ (r = 0.54, P = 0.02) and IL-2 responses at 6 weeks after immunization (r = 0.48, P = 0.04). CONCLUSION: Therapeutic HIV vaccinations led to a transient increase in decay of latently infected CD4 T cells. Further studies of therapeutic HIV vaccines may provide important insights into facilitating decay of the latent reservoir.


Asunto(s)
Vacunas contra el SIDA/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/tratamiento farmacológico , Vacunas contra el SIDA/inmunología , Infecciones por VIH/virología , Humanos , Resultado del Tratamiento , Vacunación , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/uso terapéutico , Adulto Joven
19.
AIDS Res Hum Retroviruses ; 27(8): 823-9, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21241214

RESUMEN

Nevirapine resistance mutations arise commonly following single or extended-dose nevirapine (ED-NVP) prophylaxis to prevent mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV), but decay within 6-12 months of single-dose exposure. Use of ED-NVP prophylaxis in infants is expected to rise, but data on decay of nevirapine resistance mutations in infants in whom ED-NVP failed remain limited. We assessed, in Ethiopian infants participating in the Six-Week Extended Nevirapine (SWEN) Trial, the prevalence and persistence of nevirapine resistance mutations at 6 and 12 months following single-dose or up to 6 weeks of ED-NVP, and correlated their presence with the timing of infection and the type of resistance mutations. Standard population genotyping followed by high-throughput cloning were done on dried blood spot samples collected during the trial. More infants who received ED-NVP had nevirapine resistance detected by standard population genotyping (high frequencies) at age 6 months compared with those who received single-dose nevirapine (SD-NVP) (58% of 24 vs. 26% of 19, respectively; p = 0.06). Moreover, 56% of ED-NVP-exposed infants with nevirapine resistance at age 6 months still had nevirapine resistance mutations present at high frequencies at age 1 year. Infants infected before 6 weeks of age who received either SD- or ED-NVP were more likely to have Y181C or K103N; these mutations were also more likely to persist at high frequencies through 1 year of age. HIV-infected infants in whom ED-NVP prophylaxis fails are likely to experience delayed clearance of nevirapine-resistant virus in the first year of life, which in turn places them at risk for early selection of multidrug-resistant HIV after initial therapy with nonnucleoside reverse transcriptase inhibitor-based regimens.


Asunto(s)
Frecuencia de los Genes , Infecciones por VIH , VIH-1/genética , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Nevirapina , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Inhibidores de la Transcriptasa Inversa/efectos adversos , Secuencia de Bases , Lactancia Materna , Niño , Esquema de Medicación , Farmacorresistencia Viral , Etiopía , Femenino , Genotipo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/etnología , Infecciones por VIH/prevención & control , Infecciones por VIH/transmisión , Infecciones por VIH/virología , Transcriptasa Inversa del VIH , VIH-1/efectos de los fármacos , VIH-1/crecimiento & desarrollo , Humanos , Lactante , Recién Nacido , Masculino , Datos de Secuencia Molecular , Tipificación Molecular , Mutación , Nevirapina/administración & dosificación , Nevirapina/uso terapéutico , Embarazo , Complicaciones Infecciosas del Embarazo/prevención & control , Complicaciones Infecciosas del Embarazo/virología , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Carga Viral/efectos de los fármacos
20.
PLoS One ; 4(1): e4096, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19119321

RESUMEN

BACKGROUND: Daily nevirapine (NVP) prophylaxis to HIV-exposed infants significantly reduces breast-milk HIV transmission. We assessed NVP-resistance in Indian infants enrolled in the "six-week extended-dose nevirapine" (SWEN) trial who received single-dose NVP (SD-NVP) or SWEN for prevention of breast-milk HIV transmission but who also acquired subtype C HIV infection during the first year of life. METHODS/FINDINGS: Standard population sequencing and cloning for viral subpopulations present at > or =5% frequency were used to determine HIV genotypes from 94% of the 79 infected Indian infants studied. Timing of infection was defined based on when an infant's blood sample first tested positive for HIV DNA. SWEN-exposed infants diagnosed with HIV by six weeks of age had a significantly higher prevalence of NVP-resistance than those who received SD-NVP, by both standard population sequencing (92% of 12 vs. 38% of 29; p = 0.002) and low frequency clonal analysis (92% of 12 vs. 59% of 29; p = 0.06). Likelihood of infection with NVP-resistant HIV through breast-milk among infants infected after age six weeks was substantial, but prevalence of NVP-resistance did not differ among SWEN or SD-NVP exposed infants by standard population sequencing (15% of 13 vs. 15% of 20; p = 1.00) and clonal analysis (31% of 13 vs. 40% of 20; p = 0.72). Types of NVP-resistance mutations and patterns of persistence at one year of age were similar between the two groups. NVP-resistance mutations did differ by timing of HIV infection; the Y181C variant was predominant among infants diagnosed in the first six weeks of life, compared to Y188C/H during late breast-milk transmission. CONCLUSIONS/SIGNIFICANCE: Use of SWEN to prevent breast-milk HIV transmission carries a high likelihood of resistance if infection occurs in the first six weeks of life. Moreover, there was a continued risk of transmission of NVP-resistant HIV through breastfeeding during the first year of life, but did not differ between SD-NVP and SWEN groups. As with SD-NVP, the value of preventing HIV infection in a large number of infants should be considered alongside the high risk of resistance associated with extended NVP prophylaxis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00061321.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Farmacorresistencia Viral , Infecciones por VIH/transmisión , VIH/metabolismo , Transmisión Vertical de Enfermedad Infecciosa , Leche Humana/virología , Nevirapina/uso terapéutico , Lactancia Materna/efectos adversos , Femenino , Genotipo , VIH/genética , Infecciones por VIH/prevención & control , Humanos , Lactante , Recién Nacido , Masculino , Embarazo , Complicaciones Infecciosas del Embarazo , Carga Viral
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