Web of Science: 57 cites, Scopus: 58 cites, Google Scholar: cites,
Deep Molecular Characterization of HIV-1 Dynamics under Suppressive HAART
Buzón, Maria José (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Codoñer, Francisco M. (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Frost, Simon D. W. (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Puertas, Maria C. (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Massanella, Marta (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Dalmau, Judith (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Llibre, Josep M.. (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Stevenson, Mario (University of Miami Miller School of Medicine, Miami, Florida, United States of America)
Blanco, Julià (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Clotet Sala, Bonaventura (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Paredes, Roger (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Martinez-Picado, Javier (Institució Catalana de Recerca i Estudis Avançats)
Universitat Autònoma de Barcelona

Data: 2011
Resum: In order to design strategies for eradication of HIV-1 from infected individuals, detailed insight into the HIV-1 reservoirs that persist in patients on suppressive antiretroviral therapy (ART) is required. In this regard, most studies have focused on integrated (proviral) HIV-1 DNA forms in cells circulating in blood. However, the majority of proviral DNA is replication-defective and archival, and as such, has limited ability to reveal the dynamics of the viral population that persists in patients on suppressive ART. In contrast, extrachromosomal (episomal) viral DNA is labile and as a consequence is a better surrogate for recent infection events and is able to inform on the extent to which residual replication contributes to viral reservoir maintenance. To gain insight into the diversity and compartmentalization of HIV-1 under suppressive ART, we extensively analyzed longitudinal peripheral blood mononuclear cells (PBMC) samples by deep sequencing of episomal and integrated HIV-1 DNA from patients undergoing raltegravir intensification. Reverse-transcriptase genes selectively amplified from episomal and proviral HIV-1 DNA were analyzed by deep sequencing 0, 2, 4, 12, 24 and 48 weeks after raltegravir intensification. We used maximum likelihood phylogenies and statistical tests (AMOVA and Slatkin-Maddison (SM)) in order to determine molecular compartmentalization. We observed low molecular variance (mean variability ≤0. 042). Although phylogenies showed that both DNA forms were intermingled within the phylogenetic tree, we found a statistically significant compartmentalization between episomal and proviral DNA samples (P <10 −6 AMOVA test; P = 0. 001 SM test), suggesting that they belong to different viral populations. In addition, longitudinal analysis of episomal and proviral DNA by phylogeny and AMOVA showed signs of non-chronological temporal compartmentalization (all comparisons P <10 −6) suggesting that episomal and proviral DNA forms originated from different anatomical compartments. Collectively, this suggests the presence of a chronic viral reservoir in which there is stochastic release of infectious virus and in which there are limited rounds of de novo infection. This could be explained by the existence of different reservoirs with unique pharmacological accessibility properties, which will require strategies that improve drug penetration/retention within these reservoirs in order to minimise maintenance of the viral reservoir by de novo infection. In the majority of HIV-1 positive patients, antiretroviral therapy (ART) effects a sustained reduction in plasma viremia to below detectable levels. Despite this, replication competent viruses persist and fuel viremia if antiretroviral treatment is interrupted. This viral persistence stands in the way of viral eradication through ART. While this ability to persist in the face of therapy is generally considered to be attributable to a reservoir of latently infected cells, there is debate as to how this reservoir is maintained and in particular, whether there is replenishment of the reservoir by low level, residual replication. Novel antiviral agents targeting the viral integrase offer tools to explore the viral reservoirs that persist in the face of ART and we have shown that raltegravir perturbs these reservoirs as evidenced by an accumulation of episomal DNA upon rategravir intensification (Buzon et al. , 2010). Through "deep sequencing" technology, we have longitudinally analyzed the genotypes of HIV episomes and integrated HIV DNA to evaluate whether they represent interrelated sequences or whether they have distinct origins. Statistical methods showed molecular compartmentalization, among and within episomal and integrated HIV-1 DNA samples, and suggest that episomal DNA in PBMC originates from a cellular/anatomic reservoir that is not revealed by sequencing of proviral DNA in PBMC in this study. These, and other data, suggest that ongoing replication, which can be blocked by adding raltegravir, occurs from proviruses that are genetically distinguishable from those detected at >1% frequency in these circulating blood cells.
Nota: Altres ajuts: This study was supported by the Spanish AIDS network (RD06/0006), by the HIVACAT program, by funding from the European Community's FP7/2007-2013, under the project CHAIN, by funding from the NIH to M. Stevenson and by an unrestricted grant from Merck Sharp & Dohme (MSD). J Blanco is a researcher from IGTP. MJ Buzo'n and M. Massanella were supported by AGAUR. FM Codon˜er was supported by the Marie Curie European Reintegration Grant. SDW Frost was supported in part by a Royal Society Wolfson Merit Research Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
Drets: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Llengua: Anglès
Document: Article ; recerca ; Versió publicada
Publicat a: PLOS pathogens, Vol. 7 (october 2011) , ISSN 1553-7374

DOI: 10.1371/journal.ppat.1002314
PMID: 22046128


11 p, 527.4 KB

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Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències de la salut i biociències > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
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