Origin of Minority Drug-Resistant HIV-1 Variants in Primary HIV-1 Infection

Metzner, Karin J.; Scherrer, Alexandra U.; Preiswerk, Benjamin; Joos, Béda; Wyl, Viktor von; Leemann, Christine; Rieder, Peter; Braun, Dominique L; Grube, Christina; Küster, Herbert; Böni, Jürg; Yerly, Sabine; Klimkait, Thomas; Aubert, Vincent; Furrer, Hansjakob; Battegay, Manuel; Vernazza, Pietro; Cavassini, Matthias; Calmy, Alexandra; Bernasconi, Enos; Weber, Rainer; Günthard, Huldrych F.

doi:10.1093/infdis/jit310

Cited by 34 publications

(28 citation statements)

References 42 publications

(51 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This patient participates in the Zurich Primary HIV Infection (ZPHI) study, which is an observational, open label, non-randomized, single center study (www.clinicaltrials.gov; ID NCT00537966) (21,22). Written informed consent was obtained from the patient prior to inclusion.…”

Section: Methodsmentioning

confidence: 99%

Full-length haplotype reconstruction to infer the structure of heterogeneous virus populations

et al. 2014

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Methodsmentioning

confidence: 99%

Full-length haplotype reconstruction to infer the structure of heterogeneous virus populations

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…Using ultrasensitive techniques, such as deep sequencing or allele-specific PCR, several studies have reported a high prevalence of "transmitted" minority DRM among the ART-naive population (6)(7)(8). The exact origin and clinical relevance of these minority variants carrying DRM are still debated (1,5,(8)(9)(10). We previously performed deep sequencing to detect minority DRM in blood plasma collected from 32 HIV-infected individuals during primary infection, and we found that most low-frequency DRM in our cohort were likely identified because of methodological errors or were a consequence of error-prone HIV replication in the recipient (11).…”

Section: Importancementioning

confidence: 99%

No Substantial Evidence for Sexual Transmission of Minority HIV Drug Resistance Mutations in Men Who Have Sex with Men

Chaillon

Nakazawa

Wertheim

et al. 2017

J Virol

View full text Add to dashboard Cite

During primary HIV infection, the presence of minority drug resistance mutations (DRM) may be a consequence of sexual transmission, mutations, or technical errors in identification. Baseline blood samples were collected from 24 HIV-infected antiretroviral-naive, genetically and epidemiologically linked source and recipient partners shortly after the recipient's estimated date of infection. An additional 32 longitudinal samples were available from 11 recipients. Deep sequencing of HIV reverse transcriptase (RT) was performed (Roche/454), and the sequences were screened for nucleoside and nonnucleoside RT inhibitor DRM. The likelihood of sexual transmission and persistence of DRM was assessed using Bayesian-based statistical modeling. While the majority of DRM (>20%) were consistently transmitted from source to recipient, the probability of detecting a minority DRM in the recipient was not increased when the same minority DRM was detected in the source (Bayes factor [BF] = 6.37). Longitudinal analyses revealed an exponential decay of DRM (BF = 0.05) while genetic diversity increased. Our analysis revealed no substantial evidence for sexual transmission of minority DRM (BF = 0.02). The presence of minority DRM during early infection, followed by a rapid decay, is consistent with the "mutation-selection balance" hypothesis, in which deleterious mutations are more efficiently purged later during HIV infection when the larger effective population size allows more efficient selection. Future studies using more recent sequencing technologies that are less prone to single-base errors should confirm these results by applying a similar Bayesian framework in other clinical settings. The advent of sensitive sequencing platforms has led to an increased identification of minority drug resistance mutations (DRM), including among antiretroviral therapy-naive HIV-infected individuals. While transmission of DRM may impact future therapy options for newly infected individuals, the clinical significance of the detection of minority DRM remains controversial. In the present study, we applied deep-sequencing techniques within a Bayesian hierarchical framework to a cohort of 24 transmission pairs to investigate whether minority DRM detected shortly after transmission were the consequence of (i) sexual transmission from the source, (ii) emergence shortly after infection followed by viral selection and evolution, or (iii) technical errors/limitations of deep-sequencing methods. We found no clear evidence to support the sexual transmission of minority resistant variants, and our results suggested that minor resistant variants may emerge shortly after transmission, when the small effective population size limits efficient purge by natural selection.

show abstract

“…All HIV-1 infected individuals enrolled in this study were cared for at the Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich and are participating in the Swiss HIV Cohort Study [12], and/or the Zurich Primary HIV Infection Study (ZPHI) [13,14]. The protocol for this study has been reviewed and approved by the ethics committee of the University Hospital Zurich and written informed consent was obtained from all participants.…”

Section: Ethics Statement and Participant Recruitmentmentioning

confidence: 99%

The impact of vaccination on the breadth and magnitude of the antibody response to influenza A viruses in HIV-infected individuals

Kohler¹,

Kouyos²,

Bianchi

et al. 2015

Aids

Self Cite

View full text Add to dashboard Cite

show abstract

Origin of Minority Drug-Resistant HIV-1 Variants in Primary HIV-1 Infection

Abstract: 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.

Cited by 34 publications

References 42 publications

Full-length haplotype reconstruction to infer the structure of heterogeneous virus populations

Full-length haplotype reconstruction to infer the structure of heterogeneous virus populations

No Substantial Evidence for Sexual Transmission of Minority HIV Drug Resistance Mutations in Men Who Have Sex with Men

The impact of vaccination on the breadth and magnitude of the antibody response to influenza A viruses in HIV-infected individuals

Contact Info

Product

Resources

About