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1.
PLoS Pathog ; 11(6): e1005006, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26076473

RESUMEN

[This corrects the article DOI: 10.1371/journal.ppat.1003161.].

2.
Retrovirology ; 13(1): 62, 2016 09 05.
Artículo en Inglés | MEDLINE | ID: mdl-27595568

RESUMEN

BACKGROUND: Mucosal HIV-1 transmission predominantly results in a single transmitted/founder (T/F) virus establishing infection in the new host despite the generally high genetic diversity of the transmitter virus population. To what extent HIV-1 transmission is a stochastic process or driven by selective forces that allow T/F viruses best to overcome bottlenecks in transmission has not been conclusively resolved. Building on prior investigations that suggest HIV-1 envelope (Env) features to contribute in the selection process during transmission, we compared phenotypic virus characteristics of nine HIV-1 subtype B transmission pairs, six men who have sex with men and three male-to-female transmission pairs. RESULTS: All recipients were identified early in acute infection and harbored based on extensive sequencing analysis a single T/F virus allowing a controlled analysis of virus properties in matched transmission pairs. Recipient and transmitter viruses from the closest time point to transmission showed no signs of selection for specific Env modifications such as variable loop length and glycosylation. Recipient viruses were resistant to circulating plasma antibodies of the transmitter and also showed no altered sensitivity to a large panel of entry inhibitors and neutralizing antibodies. The recipient virus did not consistently differ from the transmitter virus in terms of entry kinetics, cell-cell transmission and replicative capacity in primary cells. Our paired analysis revealed a higher sensitivity of several recipient virus isolates to interferon-α (IFNα) which suggests that resistance to IFNα cannot be a general driving force in T/F establishment. CONCLUSIONS: With the exception of increased IFNα sensitivity, none of the phenotypic virus properties we investigated clearly distinguished T/F viruses from their matched transmitter viruses supporting the notion that at least in subtype B infection HIV-1 transmission is to a considerable extent stochastic.


Asunto(s)
Infecciones por VIH/transmisión , VIH-1/genética , VIH-1/fisiología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , Enfermedad Aguda , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Femenino , Variación Genética , Infecciones por VIH/virología , VIH-1/aislamiento & purificación , Homosexualidad Masculina , Humanos , Interferón-alfa/farmacología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/virología , Masculino , Pruebas de Neutralización , Fenotipo , Análisis de Secuencia de ADN , Procesos Estocásticos , Tropismo Viral , Internalización del Virus , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología
3.
Nucleic Acids Res ; 42(14): e115, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24972832

RESUMEN

Next-generation sequencing (NGS) technologies enable new insights into the diversity of virus populations within their hosts. Diversity estimation is currently restricted to single-nucleotide variants or to local fragments of no more than a few hundred nucleotides defined by the length of sequence reads. To study complex heterogeneous virus populations comprehensively, novel methods are required that allow for complete reconstruction of the individual viral haplotypes. Here, we show that assembly of whole viral genomes of ∼8600 nucleotides length is feasible from mixtures of heterogeneous HIV-1 strains derived from defined combinations of cloned virus strains and from clinical samples of an HIV-1 superinfected individual. Haplotype reconstruction was achieved using optimized experimental protocols and computational methods for amplification, sequencing and assembly. We comparatively assessed the performance of the three NGS platforms 454 Life Sciences/Roche, Illumina and Pacific Biosciences for this task. Our results prove and delineate the feasibility of NGS-based full-length viral haplotype reconstruction and provide new tools for studying evolution and pathogenesis of viruses.


Asunto(s)
Variación Genética , VIH-1/genética , Haplotipos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Genoma Viral , Infecciones por VIH/virología , Humanos
4.
PLoS Pathog ; 9(1): e1003161, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23382686

RESUMEN

HIV-1 infects CD4+ T cells and completes its replication cycle in approximately 24 hours. We employed repeated measurements in a standardized cell system and rigorous mathematical modeling to characterize the emergence of the viral replication intermediates and their impact on the cellular transcriptional response with high temporal resolution. We observed 7,991 (73%) of the 10,958 expressed genes to be modulated in concordance with key steps of viral replication. Fifty-two percent of the overall variability in the host transcriptome was explained by linear regression on the viral life cycle. This profound perturbation of cellular physiology was investigated in the light of several regulatory mechanisms, including transcription factors, miRNAs, host-pathogen interaction, and proviral integration. Key features were validated in primary CD4+ T cells, and with viral constructs using alternative entry strategies. We propose a model of early massive cellular shutdown and progressive upregulation of the cellular machinery to complete the viral life cycle.


Asunto(s)
Linfocitos T CD4-Positivos/fisiología , Regulación Viral de la Expresión Génica , VIH-1/fisiología , Replicación Viral/genética , Linfocitos T CD4-Positivos/virología , Células HEK293 , Interacciones Huésped-Patógeno , Humanos , Modelos Estadísticos , Factores de Tiempo , Transcriptoma , Regulación hacia Arriba
5.
PLoS Comput Biol ; 10(10): e1003871, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25340797

RESUMEN

HIV-1-infected cells in peripheral blood can be grouped into different transcriptional subclasses. Quantifying the turnover of these cellular subclasses can provide important insights into the viral life cycle and the generation and maintenance of latently infected cells. We used previously published data from five patients chronically infected with HIV-1 that initiated combination antiretroviral therapy (cART). Patient-matched PCR for unspliced and multiply spliced viral RNAs combined with limiting dilution analysis provided measurements of transcriptional profiles at the single cell level. Furthermore, measurement of intracellular transcripts and extracellular virion-enclosed HIV-1 RNA allowed us to distinguish productive from non-productive cells. We developed a mathematical model describing the dynamics of plasma virus and the transcriptional subclasses of HIV-1-infected cells. Fitting the model to the data allowed us to better understand the phenotype of different transcriptional subclasses and their contribution to the overall turnover of HIV-1 before and during cART. The average number of virus-producing cells in peripheral blood is small during chronic infection. We find that a substantial fraction of cells can become defectively infected. Assuming that the infection is homogenous throughout the body, we estimate an average in vivo viral burst size on the order of 104 virions per cell. Our study provides novel quantitative insights into the turnover and development of different subclasses of HIV-1-infected cells, and indicates that cells containing solely unspliced viral RNA are a good marker for viral latency. The model illustrates how the pool of latently infected cells becomes rapidly established during the first months of acute infection and continues to increase slowly during the first years of chronic infection. Having a detailed understanding of this process will be useful for the evaluation of viral eradication strategies that aim to deplete the latent reservoir of HIV-1.


Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/genética , Leucocitos Mononucleares/virología , Modelos Genéticos , ARN Viral/genética , Antirretrovirales/farmacología , Antirretrovirales/uso terapéutico , Biología Computacional , Quimioterapia Combinada , VIH-1/efectos de los fármacos , VIH-1/metabolismo , Humanos , Leucocitos Mononucleares/clasificación , ARN Viral/sangre , ARN Viral/química , ARN Viral/metabolismo
6.
J Infect Dis ; 208(7): 1102-12, 2013 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-23847055

RESUMEN

BACKGROUND: Drug-resistant human immunodeficiency virus type 1 (HIV-1) minority variants (MVs) are present in some antiretroviral therapy (ART)-naive patients. They may result from de novo mutagenesis or transmission. To date, the latter has not been proven. METHODS: MVs were quantified by allele-specific polymerase chain reaction in 204 acute or recent seroconverters from the Zurich Primary HIV Infection study and 382 ART-naive, chronically infected patients. Phylogenetic analyses identified transmission clusters. RESULTS: Three lines of evidence were observed in support of transmission of MVs. First, potential transmitters were identified for 12 of 16 acute or recent seroconverters harboring M184V MVs. These variants were also detected in plasma and/or peripheral blood mononuclear cells at the estimated time of transmission in 3 of 4 potential transmitters who experienced virological failure accompanied by the selection of the M184V mutation before transmission. Second, prevalence between MVs harboring the frequent mutation M184V and the particularly uncommon integrase mutation N155H differed highly significantly in acute or recent seroconverters (8.2% vs 0.5%; P < .001). Third, the prevalence of less-fit M184V MVs is significantly higher in acutely or recently than in chronically HIV-1-infected patients (8.2% vs 2.5%; P = .004). CONCLUSIONS: Drug-resistant HIV-1 MVs can be transmitted. To what extent the origin-transmission vs sporadic appearance-of these variants determines their impact on ART needs to be further explored.


Asunto(s)
Farmacorresistencia Viral , Variación Genética , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/genética , Adolescente , Adulto , Anciano , Alelos , Análisis por Conglomerados , Estudios de Cohortes , Femenino , Infecciones por VIH/transmisión , VIH-1/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Filogenia , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADN , Suiza , Adulto Joven
7.
Mol Biol Evol ; 29(1): 347-57, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21890480

RESUMEN

Epidemiological processes leave a fingerprint in the pattern of genetic structure of virus populations. Here, we provide a new method to infer epidemiological parameters directly from viral sequence data. The method is based on phylogenetic analysis using a birth-death model (BDM) rather than the commonly used coalescent as the model for the epidemiological transmission of the pathogen. Using the BDM has the advantage that transmission and death rates are estimated independently and therefore enables for the first time the estimation of the basic reproductive number of the pathogen using only sequence data, without further assumptions like the average duration of infection. We apply the method to genetic data of the HIV-1 epidemic in Switzerland.


Asunto(s)
Número Básico de Reproducción , Infecciones por VIH/epidemiología , Infecciones por VIH/virología , VIH-1/genética , Modelos Biológicos , Teorema de Bayes , Humanos , Modelos Estadísticos , Filogenia
9.
Retrovirology ; 9: 27, 2012 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-22458358

RESUMEN

BACKGROUND: The various classes of small noncoding RNAs (sncRNAs) are important regulators of gene expression across divergent types of organisms. While a rapidly increasing number of sncRNAs has been identified over recent years, the isolation of sncRNAs of low abundance remains challenging. Virally encoded sncRNAs, particularly those of RNA viruses, can be expressed at very low levels. This is best illustrated by HIV-1 where virus encoded sncRNAs represent approximately 0.1-1.0% of all sncRNAs in HIV-1 infected cells or were found to be undetected. Thus, we applied a novel, sequence targeted enrichment strategy to capture HIV-1 derived sncRNAs in HIV-1 infected primary CD4+ T-lymphocytes and macrophages that allows a greater than 100-fold enrichment of low abundant sncRNAs. RESULTS: Eight hundred and ninety-two individual HIV-1 sncRNAs were cloned and sequenced from nine different sncRNA libraries derived from five independent experiments. These clones represent up to 90% of all sncRNA clones in the generated libraries. Two hundred and sixteen HIV-1 sncRNAs were distinguishable as unique clones. They are spread throughout the HIV-1 genome, however, forming certain clusters, and almost 10% show an antisense orientation. The length of HIV-1 sncRNAs varies between 16 and 89 nucleotides with an unexpected peak at 31 to 50 nucleotides, thus, longer than cellular microRNAs or short-interfering RNAs (siRNAs). Exemplary HIV-1 sncRNAs were also generated in cells infected with different primary HIV-1 isolates and can inhibit HIV-1 replication. CONCLUSIONS: HIV-1 infected cells generate virally encoded sncRNAs, which might play a role in the HIV-1 life cycle. Furthermore, the enormous capacity to enrich low abundance sncRNAs in a sequence specific manner highly recommends our selection strategy for any type of investigation where origin or target sequences of the sought-after sncRNAs are known.


Asunto(s)
Linfocitos T CD4-Positivos/virología , Regulación Viral de la Expresión Génica , VIH-1/patogenicidad , Macrófagos/virología , ARN Pequeño no Traducido/metabolismo , Células Cultivadas , VIH-1/genética , Humanos , ARN Pequeño no Traducido/genética , ARN Viral/genética , ARN Viral/metabolismo
10.
Nat Med ; 11(6): 615-22, 2005 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15880120

RESUMEN

To determine the protective potential of the humoral immune response against HIV-1 in vivo we evaluated the potency of three neutralizing antibodies (2G12, 2F5 and 4E10) in suppressing viral rebound in six acutely and eight chronically HIV-1-infected individuals undergoing interruption of antiretroviral treatment (ART). Only two of eight chronically infected individuals showed evidence of a delay in viral rebound during the passive immunization. Rebound in antibody-treated acutely infected individuals upon cessation of ART was substantially later than in a control group of 12 individuals with acute infection. Escape mutant analysis showed that the activity of 2G12 was crucial for the in vivo effect of the neutralizing antibody cocktail. By providing further direct evidence of the potency, breadth and titers of neutralizing antibodies that are required for in vivo activity, these data underline both the potential and the limits of humoral immunity in controlling HIV-1 infection.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Anti-VIH/uso terapéutico , Infecciones por VIH/terapia , VIH-1/inmunología , Enfermedad Aguda , Adulto , Fármacos Anti-VIH/administración & dosificación , Enfermedad Crónica , Femenino , VIH-1/genética , VIH-1/fisiología , Humanos , Inmunización Pasiva , Masculino , Persona de Mediana Edad , Mutación , Carga Viral , Replicación Viral
11.
J Infect Dis ; 203(6): 791-7, 2011 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-21285456

RESUMEN

The 69 insertion and Q151M mutations are multi-nucleoside/nucleotide resistance mutations (MNR). The prevalence among 4078 antiretroviral therapy (ART)-experienced individuals was <1.3%. Combined ART fully prevented MNR in subtype B infections. Case-control studies were performed to identify risk factors. Control subjects were patients with ≥ 3 thymidine-analogue mutations. The 69 insertion study (27 control subjects, 14 case patients) identified didanosine exposure as a risk (odds ratio, 5.0 per year; P = .019), whereas the Q151M study (which included 44 control subjects and 25 case patients) detected no associations. Following detection, individuals with Q151M tended to have lower suppression rates and higher mortality rates, relative to control subjects. Additional studies are needed to verify these findings in non-subtype B infections.


Asunto(s)
Farmacorresistencia Viral Múltiple/genética , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/mortalidad , VIH-1/efectos de los fármacos , Mutación , Fármacos Anti-VIH/farmacología , Antirretrovirales/farmacología , Antirretrovirales/uso terapéutico , Estudios de Casos y Controles , Causas de Muerte , Estudios de Cohortes , Didanosina/farmacología , VIH-1/genética , Humanos , Modelos Logísticos , Factores de Riesgo , Suiza/epidemiología , Resultado del Tratamiento
12.
Viruses ; 14(2)2022 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-35215999

RESUMEN

Little is known about whether and how variation in the HIV-1 genome affects its transmissibility. Assessing which genomic features of HIV-1 are under positive or negative selection during transmission is challenging, because very few virus particles are typically transmitted, and random genetic drift can dilute genetic signals in the recipient virus population. We analyzed 30 transmitter-recipient pairs from the Zurich Primary HIV Infection Study and the Swiss HIV Cohort Study using near full-length HIV-1 genomes. We developed a new statistical test to detect selection during transmission, called Selection Test in Transmission (SeTesT), based on comparing the transmitter and recipient virus population and accounting for the transmission bottleneck. We performed extensive simulations and found that sensitivity of detecting selection during transmission is limited by the strong population bottleneck of few transmitted virions. When pooling individual test results across patients, we found two candidate HIV-1 genomic features for affecting transmission, namely amino acid positions 3 and 18 of Vpu, which were significant before but not after correction for multiple testing. In summary, SeTesT provides a general framework for detecting selection based on genomic sequencing data of transmitted viruses. Our study shows that a higher number of transmitter-recipient pairs is required to improve sensitivity of detecting selection.


Asunto(s)
Infecciones por VIH/transmisión , VIH-1/genética , Heterosexualidad , Selección Genética , Transmisión de Enfermedad Infecciosa/estadística & datos numéricos , Femenino , Variación Genética , Proteínas del Virus de la Inmunodeficiencia Humana/genética , Humanos , Masculino , Modelos Estadísticos , Datos de Secuencia Molecular , Mutación Puntual
13.
Clin Infect Dis ; 53(12): 1271-9, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21998286

RESUMEN

BACKGROUND: In the context of sexual transmission of human immunodeficiency virus type 1 (HIV-1), current findings suggest that the mucosal barrier is the major site of viral selection, transforming the complex inoculum to a small, homogeneous founder virus population. We analyzed HIV-1 transmission in relation to viral and host characteristics within the Zurich primary HIV-1 infection study. METHODS: Clonal HIV-1 envelope sequences (on average 16 clones/patient) were isolated from the first available plasma samples during the early phase of infection from 145 patients with primary HIV-1 infection. Phylogenetic and tropism analyses were performed. Differences of viral diversities were investigated in association with several parameters potentially influencing HIV-1 transmission, eg, concomitant sexually transmitted infections (STIs) and mode of transmission. RESULTS: Median viral diversity within env C2-V3-C3 region was 0.39% (range 0.04%-3.23%). Viral diversity did not correlate with viral load, but it was slightly correlated with the duration of infection. Neither transmission mode, gender, nor STI predicted transmission of more heterogeneous founder virus populations that were found in 16 of 145 patients (11%; diversity >1%). Only 2 patients (1.4%) were assuredly infected with CXCR4-tropic HIV-1 within a R5/X4-tropic--mixed population, as revealed and confirmed using several genotypic prediction algorithms and phenotypic assays. CONCLUSIONS: Our findings suggest that transmission of multiple HIV-1 variants might be a complex process that is not dependent on mucosal factors alone. CXCR4-tropic viruses can be sexually transmitted in rare instances, but their clinical relevance remains to be determined.


Asunto(s)
Variación Genética , Infecciones por VIH/transmisión , Infecciones por VIH/virología , VIH-1/fisiología , Tropismo Viral , Adulto , Anciano , Análisis por Conglomerados , Femenino , VIH-1/genética , VIH-1/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Filogenia , Análisis de Secuencia de ADN , Suiza , Adulto Joven , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética
14.
Clin Infect Dis ; 52(4): 532-9, 2011 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-21220770

RESUMEN

BACKGROUND: The time passed since the infection of a human immunodeficiency virus (HIV)-infected individual (the age of infection) is an important but often only poorly known quantity. We assessed whether the fraction of ambiguous nucleotides obtained from bulk sequencing as done for genotypic resistance testing can serve as a proxy of this parameter. METHODS: We correlated the age of infection and the fraction of ambiguous nucleotides in partial pol sequences of HIV-1 sampled before initiation of antiretroviral therapy (ART). Three groups of Swiss HIV Cohort Study participants were analyzed, for whom the age of infection was estimated on the basis of Bayesian back calculation (n = 3,307), seroconversion (n = 366), or diagnoses of primary HIV infection (n = 130). In addition, we studied 124 patients for whom longitudinal genotypic resistance testing was performed while they were still ART-naïve. RESULTS: We found that the fraction of ambiguous nucleotides increased with the age of infection with a rate of .2% per year within the first 8 years but thereafter with a decreasing rate. We show that this pattern is consistent with population-genetic models for realistic parameters. Finally, we show that, in this highly representative population, a fraction of ambiguous nucleotides of >.5% provides strong evidence against a recent infection event <1 year prior to sampling (negative predictive value, 98.7%). CONCLUSIONS: These findings show that the fraction of ambiguous nucleotides is a useful marker for the age of infection.


Asunto(s)
Infecciones por VIH/virología , VIH-1/clasificación , VIH-1/genética , Polimorfismo Genético , Adulto , Estudios de Cohortes , Femenino , VIH-1/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia de ADN , Suiza , Factores de Tiempo , Productos del Gen pol del Virus de la Inmunodeficiencia Humana/genética
15.
Proc Natl Acad Sci U S A ; 105(43): 16725-30, 2008 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-18936487

RESUMEN

Rapid rebound of plasma viremia in patients after interruption of long-term combination antiretroviral therapy (cART) suggests persistence of low-level replicating cells or rapid reactivation of latently infected cells. To further characterize rebounding virus, we performed extensive longitudinal clonal evolutionary studies of HIV env C2-V3-C3 regions and exploited the temporal relationships of rebounding plasma viruses with regard to pretreatment sequences in 20 chronically HIV-1-infected patients having undergone multiple 2-week structured treatment interruptions (STI). Rebounding virus during the short STI was homogeneous, suggesting mono- or oligoclonal origin during reactivation. No evidence for a temporal structure of rebounding virus in regard to pretreatment sequences was found. Furthermore, expansion of distinct lineages at different STI cycles emerged. Together, these findings imply stochastic reactivation of different clones from long-lived latently infected cells rather than expansion of viral populations replicating at low levels. After treatment was stopped, diversity increased steadily, but pretreatment diversity was, on average, achieved only >2.5 years after the start of STI when marked divergence from preexisting quasispecies also emerged. In summary, our results argue against persistence of ongoing low-level replication in patients on suppressive cART. Furthermore, a prolonged delay in restoration of pretreatment viral diversity after treatment interruption demonstrates a surprisingly sustained evolutionary bottleneck induced by punctuated antiretroviral therapy.


Asunto(s)
Infecciones por VIH/virología , VIH/fisiología , Activación Viral , Latencia del Virus/efectos de los fármacos , Células Cultivadas , Variación Genética , VIH/genética , Infecciones por VIH/tratamiento farmacológico , Humanos , Datos de Secuencia Molecular , Filogenia , Receptores CXCR4 , Receptores del VIH , Replicación Viral/efectos de los fármacos
16.
J Virol ; 82(3): 1591-9, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18032508

RESUMEN

The definition of plasma neutralizing antibody titers capable of controlling human immunodeficiency virus (HIV) infection in vivo is considered a critical step in vaccine development. Here we provide estimates for effective neutralization titers by assessing samples from a recent passive immunization trial with the neutralizing monoclonal antibodies (MAbs) 2G12, 2F5, and 4E10 using an analytic strategy that dissects the contributions of these MAbs to the total neutralization activity in patient plasma. Assessment of neutralization activities for six responding patients with partial or complete control of viremia during the MAb treatment and for the eight nonresponding patients revealed a significant difference between these groups: Among responders, MAb-mediated activity exceeded the autologous neutralization response by 1 to 2 log units (median difference, 43.3-fold), while in the nonresponder group, the autologous activity prevailed (median difference, 0.63-fold). In order to reach a 50% proportion of the responders in our study cohort, MAb neutralizing titers higher than 1:200 were required based on this analysis. The disease stage appears to have a significant impact on the quantities needed, since titers above 1:1,000 were needed to reach the same effect in chronic infection. Although our analysis is based on very small sample numbers and thus cannot be conclusive, our data provide a first estimate on how in vitro-measured neutralizing antibody activity can relate to in vivo efficacy in controlling HIV infection and may therefore provide valuable information for vaccine development. Interestingly, lower neutralizing antibody levels showed an effect in acute compared to chronic infection, suggesting that in early disease stages, therapeutic vaccination may show promise. Equally, this raises hopes that a preventive vaccine could become effective at comparatively lower neutralizing antibody titers.


Asunto(s)
Anticuerpos Monoclonales/inmunología , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/inmunología , Inmunización Pasiva/métodos , Anticuerpos Monoclonales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Humanos , Pruebas de Neutralización , Estadística como Asunto , Viremia
17.
Retrovirology ; 5: 107, 2008 Nov 26.
Artículo en Inglés | MEDLINE | ID: mdl-19036147

RESUMEN

BACKGROUND: Mathematical models based on kinetics of HIV-1 plasma viremia after initiation of combination antiretroviral therapy (cART) inferred HIV-infected cells to decay exponentially with constant rates correlated to their strength of virus production. To further define in vivo decay kinetics of HIV-1 infected cells experimentally, we assessed infected cell-classes of distinct viral transcriptional activity in peripheral blood mononuclear cells (PBMC) of five patients during 1 year after initiation of cART RESULTS: In a novel analytical approach patient-matched PCR for unspliced and multiply spliced viral RNAs was combined with limiting dilution analysis at the single cell level. This revealed that HIV-RNA+ PBMC can be stratified into four distinct viral transcriptional classes. Two overlapping cell-classes of high viral transcriptional activity, suggestive of a virion producing phenotype, rapidly declined to undetectable levels. Two cell classes expressing HIV-RNA at low and intermediate levels, presumably insufficient for virus production and occurring at frequencies exceeding those of productively infected cells matched definitions of HIV-latency. These cells persisted during cART. Nevertheless, during the first four weeks of therapy their kinetics resembled that of productively infected cells. CONCLUSION: We have observed biphasic decays of latently HIV-infected cells of low and intermediate viral transcriptional activity with marked decreases in cell numbers shortly after initiation of therapy and complete persistence in later phases. A similar decay pattern was shared by cells with greatly enhanced viral transcriptional activity which showed a certain grade of levelling off before their disappearance. Thus it is conceivable that turnover/decay rates of HIV-infected PBMC may be intrinsically variable. In particular they might be accelerated by HIV-induced activation and reactivation of the viral life cycle and slowed down by the disappearance of such feedback-loops after initiation of cART.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/crecimiento & desarrollo , Leucocitos Mononucleares/virología , Carga Viral , VIH-1/efectos de los fármacos , Humanos
18.
AIDS ; 18(14): 1951-3, 2004 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-15353981

RESUMEN

In HIV-1-infected patients with long-term undetectable viraemia on highly active antiretroviral treatment (HAART), we found that pre-HAART plasma viraemia and the baseline proviral DNA level were significantly associated with the viraemia setpoint during scheduled treatment interruptions. In long-term treated patients, pre-HAART viraemia may not be available, and in these circumstances proviral DNA, measured at the time of scheduled treatment interruption, can help to identify patients likely to reach a low viraemia setpoint after treatment interruption.


Asunto(s)
ADN Viral , Infecciones por VIH/genética , VIH-1/genética , Terapia Antirretroviral Altamente Activa , Estudios de Cohortes , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Humanos , Análisis Multivariante , Mutación/genética , ARN Viral/genética , Viremia/genética , Viremia/virología
19.
AIDS ; 17(2): 195-9, 2003 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-12545079

RESUMEN

OBJECTIVE: To evaluate time to viral rebound in patients undergoing repeated structured treatment interruptions (STI). METHOD: Fourteen chronically HIV-infected patients enrolled in the Swiss-Spanish Intermittent Treatment Trial (SSITT) underwent frequent blood sampling. Patients underwent four cycles of 2-week STI, followed by 8-week retreatment with the identical antiretroviral treatment (HAART) used before STI. At the fifth cycle, treatment was stopped for a longer period. Before each new STI, plasma viral load (VL) had to reach < 50 copies/ml. VL was measured during day 0 (last day on HAART) and on days 4, 8 and 14 during all five STI. RESULTS: During the first cycle, plasma HIV RNA increased to > 50 copies/ml (range, 67-88) in five patients at day 4, in eight patients (> 100 copies/ml) at day 8 and in 12 patients (> 100 copies/ml) at day 14. Cumulative analysis of the frequency of detectable HIV RNA at days 4, 8 and 14 compared with day 0 for all five cycles revealed nine patients with VL > 50 copies/ml [13 of 54 samples tested (24.1%); = 0.14] at day 4, 11 patients [33 of 58 samples tested (56.9%); < 0.0001] at day 8 and 12 patients [53 of 65 samples tested (81.5%); < 0.0001] at day 14. CONCLUSIONS: Significant viral replication can be induced during 1 week STI, and this may increase the risk of the emergence of drug resistance during long-term cycling. Therefore, short-term cycling strategies such as 1-week-on, 1-week-off treatment, although conceptually intriguing, should still be regarded as investigational and should be restricted to rigorously controlled clinical trials ideally involving patients who have never failed treatment before.


Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , VIH/fisiología , ARN Viral/sangre , Terapia Antirretroviral Altamente Activa/métodos , Esquema de Medicación , Infecciones por VIH/virología , Humanos , Viremia/virología , Latencia del Virus , Replicación Viral/efectos de los fármacos
20.
Antivir Ther ; 7(2): 91-103, 2002 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12212929

RESUMEN

Unspliced HIV-RNA (HIV-UsRNA) associated with peripheral blood mononuclear cells (PBMCs) persists in patients on potent antiretroviral therapy even in the absence of detectable plasma HIV-RNA. To further characterize such residual HIV-RNA, cell-associated virion-encapsidated HIV and intracellular unspliced HIV-RNA were differentiated and monitored using a novel highly sensitive method. In addition, expression of HIV-mRNA encoding tat and rev was assessed. PBMCs of patients with unsuppressed plasma viraemia harboured an extracellular fraction of HIV-UsRNA, which correlated highly with intracellular HIV-RNA levels. Thus, extracellular PBMC-associated HIV-RNA may, to a significant extent, reflect nascent virions attached to productively infected cells. Upon treatment with potent antiretroviral therapy resulting in plasma viraemia <50 copies/ml, expression of cell-associated viral particles was hardly discernible in PBMCs but transcription of unspliced HIV-RNA persisted. Given the virtual absence of rev-mRNA, translation of residual HIV-UsRNA was probably precluded by retention of these transcripts in the nucleus. As shown by limiting dilution analysis, HIV-1 infected cells with such a repressed viral transcription pattern were observed at high frequencies in PBMC from untreated patients.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Leucocitos Mononucleares/virología , ARN Viral/sangre , Línea Celular , Estudios de Cohortes , Genes rev , Genes tat , Infecciones por VIH/sangre , Infecciones por VIH/virología , Humanos , ARN Mensajero/análisis
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