Viral Diversity Based on Next-Generation Sequencing of HIV-1 Provides Precise Estimates of Infection Recency and Time Since Infection

Carlisle, Louisa; Turk, Teja; Kusejko, Katharina; Metzner, Karin J.; Leemann, Christine; Schenkel, Corinne D.; Bachmann, Nadine; Posada, Susana; Beerenwinkel, Niko; Böni, Jürg; Yerly, Sabine; Klimkait, Thomas; Perreau, Matthieu; Braun, Dominique L; Rauch, Andri; Calmy, Alexandra; Cavassini, Matthias; Battegay, Manuel; Vernazza, Pietro; Bernasconi, Enos; Günthard, Huldrych F.; Kouyos, Roger D.

doi:10.1093/infdis/jiz094

Cited by 29 publications

(33 citation statements)

References 37 publications

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“…This study was limited by the number of samples available, which were all from patients already infected with HIV-1 at the time of HCV sampling, and primarily from men who have sex with men (MSM) with no recorded history of intravenous drug use (60/72 patients). The small sample size (and especially the small number of patients with large infection times) prevented the examination of non-linear effects, such as a potential saturation of diversity at large infection times, which has been observed for HIV-1 [14,18]. Furthermore, the presence of HIV-1 may affect the diversification of HCV over time, given the known impact of HIV-1 infection on HCV infection [31][32][33], and the increased virus load of HCV in the presence of HIV-1 [34][35][36].…”

Section: Discussionmentioning

confidence: 99%

“…Average pairwise diversity (APD) was calculated from nucleotide minority variant frequencies using Equation (1) [17], explanation as in [18]. This first determines whether a position has minor variants above a threshold, and subsequently sums the diversity contribution of all variants at that position.…”

Section: Diversity Score Calculationmentioning

confidence: 99%

“…A similar problem exists for human immunodeficiency virus-1 (HIV-1), which is also an RNA virus of comparable genome size that chronically infects patients. For HIV-1, it has been shown that viral diversity can be used to infer infection recency [14][15][16] and time since infection [17], and that diversity derived from next-generation sequencing (NGS) sequences is more accurate than diversity derived as the fraction of ambiguous nucleotides from Sanger sequences [18].…”

Section: Introductionmentioning

confidence: 99%

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HCV Genetic Diversity Can Be Used to Infer Infection Recency and Time since Infection

Carlisle

Turk

Metzner

et al. 2020

Viruses

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HIV-1 genetic diversity can be used to infer time since infection (TSI) and infection recency. We adapted this approach for HCV and identified genomic regions with informative diversity. We included 72 HCV/HIV-1 coinfected participants of the Swiss HIV Cohort Study, for whom reliable estimates of infection date and viral sequences were available. Average pairwise diversity (APD) was calculated over each codon position for the entire open reading frame of HCV. Utilizing cross validation, we evaluated the correlation of APD with TSI, and its ability to infer TSI via a linear model. We additionally studied the ability of diversity to classify infections as recent (infected for <1 year) or chronic, using receiver-operator-characteristic area under the curve (ROC-AUC) in 50 patients whose infection could be unambiguously classified as either recent or chronic. Measuring HCV diversity over third or all codon positions gave similar performances, and notable improvement over first or second codon positions. APD calculated over the entire genome enabled classification of infection recency (ROC-AUC = 0.76). Additionally, APD correlated with TSI (R2 = 0.33) and could predict TSI (mean absolute error = 1.67 years). Restricting the region over which APD was calculated to E2-NS2 further improved accuracy (ROC-AUC = 0.85, R2 = 0.54, mean absolute error = 1.38 years). Genetic diversity in HCV correlates with TSI and is a proxy for infection recency and TSI, even several years post-infection.

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Section: Discussionmentioning

confidence: 99%

Section: Diversity Score Calculationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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HCV Genetic Diversity Can Be Used to Infer Infection Recency and Time since Infection

Carlisle

Turk

Metzner

et al. 2020

Viruses

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“…The accuracy of the estimations was improved by increasing the sequence depth and particularly viral diversity in the 3 rd codon position increased linearly with time (11). NGS data are superior to the fraction of ambiguous sites or Sanger sequencing (11, 12). Moreover, NGS does not require heterochronous sampling and this provides an additional strength of this method.…”

Section: Discussionmentioning

confidence: 99%

Validation of molecular clock inferred HIV infection ages: evidence for accurate estimation of infection dates

Kostaki

Limnaios

Roussos

et al. 2020

Preprint

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Improving HIV diagnosis, access to care and effective antiretroviral treatment provides our global strategy to reduce HIV incidence. To reach this goal we need to increase our knowledge about local epidemics. HIV infection dates would be an important information towards this goal, but they are largely unknown. To date, methods to estimate the dates of HIV infection are based mainly on laboratory or molecular methods. Our aim was to validate molecular clock inferred infection dates that were estimated by analysing sequences from 145 people living with HIV (PLHIV) with known transmission dates (clinically estimated infection dates). All HIV sequences were obtained by Sanger sequencing and were previously found to belong to well-established molecular transmission clusters (MTCs). Our analysis showed that the molecular clock inferred infection dates were correlated with the clinically estimated ones (Spearman’s Correlation coefficient = 0.93, p<0.001) and that there was an agreement between them (Lin’s concordance correlation coefficient = 0.92, p<0.001). For most cases (61.4%), the molecular clock inferred preceded the clinically estimated infection dates. The median difference between clinically and molecularly estimated dates of infection was of 0.18 (IQR: -0.21, 0.89) years. The lowest differences were identified in people who inject drugs of our study population. Our study shows that the estimated time to more recent common ancestor (tMRCA) of nodes within clusters provides a reliable approximation of HIV infections for PLHIV infected within MTCs. Next-generation sequencing data and molecular clock estimates based on heterochronous sequences provide, probably, more reliable methods for inferring infection dates. However, since these data are not available in most of the HIV clinical laboratories, our approach, under specific conditions, can provide a reliable estimation of HIV infection dates and can be used for HIV public health interventions.

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“…Viral diversity from next-generation sequencing of HIV-1 samples provides more exact and precise estimates of time since infection, consequently, the infection regencies are also crucial for HIV-1 surveillance and understanding of viral pathogenesis. NGS-derived average pair-wise diversity exhibited higher sensitivity and specificity compared to fraction of ambiguous nucleotides (Carlisle et al 2019).…”

Section: Next-generation Sequencing (Ngs)-based Immunodetectionmentioning

confidence: 99%

Advanced Immunotechnological Methods for Detection and Diagnosis of Viral Infections: Current Applications and Future Challenges

Bramhachari

Sheela

Prathyusha

et al. 2020

Dynamics of Immune Activation in Viral Diseases

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Diagnosis and identification of viruses is an important component of diagnostic virology laboratory. Although various modes of diagnostic methods are now available at disposal, a vast majority of the diseases across the globe remain undiagnosed. This is largely due to the overlapping undifferentiated set of symptoms across myriad set of RNA and DNA viral diseases. As such, it becomes critical to take into consideration several factors for viral diagnosis ranging from the type and quality of specimen collected, time of specimen collection, mode of transport, accuracy, specificity, sensitivity, and the type of diagnostic method used. This chapter broadly emphasizes various methods on diagnostic virology ranging from the classical methods of diagnosis to the most recently developed molecular methods of detection of virus.

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Viral Diversity Based on Next-Generation Sequencing of HIV-1 Provides Precise Estimates of Infection Recency and Time Since Infection

Abstract: With mean absolute error below one year HIV genetic diversity derived from NGS sequencing is both superior estimator of time since infection and superior classifier of infection recency compared to the genetic diversity calculated from Sanger sequencing.

Cited by 29 publications

References 37 publications

HCV Genetic Diversity Can Be Used to Infer Infection Recency and Time since Infection

HCV Genetic Diversity Can Be Used to Infer Infection Recency and Time since Infection

Validation of molecular clock inferred HIV infection ages: evidence for accurate estimation of infection dates

Advanced Immunotechnological Methods for Detection and Diagnosis of Viral Infections: Current Applications and Future Challenges

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