Deep molecular characterization of hiv-1 dynamics under suppressive haart

Maria J. Buzón, Francisco M. Codoñer, Simon D W Frost, Christian Pou, Maria C. Puertas, Marta Massanella, Judith Dalmau, Josep M. Llibre, Mario Stevenson, Julià Blanco, Bonaventura Clotet, Roger Paredes, Javier Martinez-Picado

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere1002314
JournalPLoS Pathogens
Volume7
Issue number10
DOIs
StatePublished - Oct 1 2011

Fingerprint

HIV-1
DNA
Phylogeny
High-Throughput Nucleotide Sequencing
Infection
Maintenance
Virus Release
RNA-Directed DNA Polymerase
Viral DNA
Population Dynamics
DNA Replication
Blood Cells
Therapeutics
Pharmacology
Pharmaceutical Preparations
Population
Genes
Raltegravir Potassium

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Buzón, M. J., Codoñer, F. M., Frost, S. D. W., Pou, C., Puertas, M. C., Massanella, M., ... Martinez-Picado, J. (2011). Deep molecular characterization of hiv-1 dynamics under suppressive haart. PLoS Pathogens, 7(10), [e1002314]. https://doi.org/10.1371/journal.ppat.1002314

Deep molecular characterization of hiv-1 dynamics under suppressive haart. / Buzón, Maria J.; Codoñer, Francisco M.; Frost, Simon D W; Pou, Christian; Puertas, Maria C.; Massanella, Marta; Dalmau, Judith; Llibre, Josep M.; Stevenson, Mario; Blanco, Julià; Clotet, Bonaventura; Paredes, Roger; Martinez-Picado, Javier.

In: PLoS Pathogens, Vol. 7, No. 10, e1002314, 01.10.2011.

Research output: Contribution to journalArticle

Buzón, MJ, Codoñer, FM, Frost, SDW, Pou, C, Puertas, MC, Massanella, M, Dalmau, J, Llibre, JM, Stevenson, M, Blanco, J, Clotet, B, Paredes, R & Martinez-Picado, J 2011, 'Deep molecular characterization of hiv-1 dynamics under suppressive haart', PLoS Pathogens, vol. 7, no. 10, e1002314. https://doi.org/10.1371/journal.ppat.1002314
Buzón MJ, Codoñer FM, Frost SDW, Pou C, Puertas MC, Massanella M et al. Deep molecular characterization of hiv-1 dynamics under suppressive haart. PLoS Pathogens. 2011 Oct 1;7(10). e1002314. https://doi.org/10.1371/journal.ppat.1002314
Buzón, Maria J. ; Codoñer, Francisco M. ; Frost, Simon D W ; Pou, Christian ; Puertas, Maria C. ; Massanella, Marta ; Dalmau, Judith ; Llibre, Josep M. ; Stevenson, Mario ; Blanco, Julià ; Clotet, Bonaventura ; Paredes, Roger ; Martinez-Picado, Javier. / Deep molecular characterization of hiv-1 dynamics under suppressive haart. In: PLoS Pathogens. 2011 ; Vol. 7, No. 10.
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