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Impact of the HIV-1 genetic background and HIV-1 population size on the evolution of raltegravir resistance

Overview of attention for article published in Retrovirology, January 2018
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Title
Impact of the HIV-1 genetic background and HIV-1 population size on the evolution of raltegravir resistance
Published in
Retrovirology, January 2018
DOI 10.1186/s12977-017-0384-z
Pubmed ID
Authors

Axel Fun, Thomas Leitner, Linos Vandekerckhove, Martin Däumer, Alexander Thielen, Bernd Buchholz, Andy I. M. Hoepelman, Elizabeth H. Gisolf, Pauline J. Schipper, Annemarie M. J. Wensing, Monique Nijhuis

Abstract

Emergence of resistance against integrase inhibitor raltegravir in human immunodeficiency virus type 1 (HIV-1) patients is generally associated with selection of one of three signature mutations: Y143C/R, Q148K/H/R or N155H, representing three distinct resistance pathways. The mechanisms that drive selection of a specific pathway are still poorly understood. We investigated the impact of the HIV-1 genetic background and population dynamics on the emergence of raltegravir resistance. Using deep sequencing we analyzed the integrase coding sequence (CDS) in longitudinal samples from five patients who initiated raltegravir plus optimized background therapy at viral loads > 5000 copies/ml. To investigate the role of the HIV-1 genetic background we created recombinant viruses containing the viral integrase coding region from pre-raltegravir samples from two patients in whom raltegravir resistance developed through different pathways. The in vitro selections performed with these recombinant viruses were designed to mimic natural population bottlenecks. Deep sequencing analysis of the viral integrase CDS revealed that the virological response to raltegravir containing therapy inversely correlated with the relative amount of unique sequence variants that emerged suggesting diversifying selection during drug pressure. In 4/5 patients multiple signature mutations representing different resistance pathways were observed. Interestingly, the resistant population can consist of a single resistant variant that completely dominates the population but also of multiple variants from different resistance pathways that coexist in the viral population. We also found evidence for increased diversification after stronger bottlenecks. In vitro selections with low viral titers, mimicking population bottlenecks, revealed that both recombinant viruses and HXB2 reference virus were able to select mutations from different resistance pathways, although typically only one resistance pathway emerged in each individual culture. The generation of a specific raltegravir resistant variant is not predisposed in the genetic background of the viral integrase CDS. Typically, in the early phases of therapy failure the sequence space is explored and multiple resistance pathways emerge and then compete for dominance which frequently results in a switch of the dominant population over time towards the fittest variant or even multiple variants of similar fitness that can coexist in the viral population.

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Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 25 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 25 100%

Demographic breakdown

Readers by professional status Count As %
Student > Master 7 28%
Student > Bachelor 2 8%
Researcher 2 8%
Lecturer 1 4%
Student > Ph. D. Student 1 4%
Other 3 12%
Unknown 9 36%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 5 20%
Medicine and Dentistry 4 16%
Immunology and Microbiology 2 8%
Agricultural and Biological Sciences 1 4%
Chemical Engineering 1 4%
Other 2 8%
Unknown 10 40%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 06 February 2018.
All research outputs
#14,088,972
of 23,015,156 outputs
Outputs from Retrovirology
#667
of 1,108 outputs
Outputs of similar age
#232,720
of 441,866 outputs
Outputs of similar age from Retrovirology
#20
of 29 outputs
Altmetric has tracked 23,015,156 research outputs across all sources so far. This one is in the 37th percentile – i.e., 37% of other outputs scored the same or lower than it.
So far Altmetric has tracked 1,108 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 7.1. This one is in the 37th percentile – i.e., 37% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 441,866 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 45th percentile – i.e., 45% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 29 others from the same source and published within six weeks on either side of this one. This one is in the 27th percentile – i.e., 27% of its contemporaries scored the same or lower than it.