Surreal illustration of reconstructed HIV genome.

Decoding HIV: How New Tech Reconstructs Viral Genomes with Shiver

Beau Callahan in Health & Wellness August 2025 • 4 min read.

"Unlocking the secrets of HIV evolution with advanced sequencing: A breakthrough in genomic analysis for better understanding and treatment."

Understanding how viruses evolve is critical for developing effective treatments and prevention strategies. For HIV, this understanding hinges on analyzing its genetic sequence data. The more accurate this data, the better we can interpret the subtle but significant differences between viral strains.

Next-generation sequencing (NGS) offers incredible potential with its high throughput and detailed analysis of minority variants. However, its widespread adoption for HIV research has been hampered by the difficulty of accurately reconstructing the consensus sequence of a quasispecies – a population of closely related viral variants within a single individual. The presence of high diversity, frequent insertions, and deletions (indels) makes this a significant challenge.

Researchers have developed a new tool called 'shiver' to overcome these obstacles. Shiver pre-processes reads (short fragments of DNA) for quality and removes contamination, then maps them to a reference genome tailored to the specific sample. This approach minimizes bias and maximizes the accuracy of reconstruction, even in highly diverse HIV samples.

Shiver: Reconstructing HIV Genomes with Precision

Surreal illustration of reconstructed HIV genome.

The core innovation of shiver lies in its ability to create a customized reference genome for each sample. Traditional methods often rely on mapping reads to a standard reference sequence, which can lead to biased data loss, especially in regions with high variability or indels. Shiver avoids this by:

The process involves assembling reads into contigs (contiguous sequences), correcting those contigs, and then filling gaps using the closest identified existing reference sequences. This tailored reference minimizes mapping errors and ensures that even highly divergent reads are accurately aligned.

Quality Control: Thoroughly pre-processes reads to remove low-quality data and contaminants.
De Novo Assembly: Aligns reads to themselves to create contigs, capturing the unique genetic information of the sample.
Contig Correction: Corrects splicing and orientation of contigs to ensure accurate representation of the viral genome.
Customized Reference: Uses corrected contigs to build a reference genome tailored to the sample, minimizing bias during mapping.
Accurate Mapping: Maps reads to the constructed reference, enabling precise consensus sequence reconstruction and minority variant analysis.

The researchers validated shiver using both publicly available datasets and newly generated samples, demonstrating its superiority over traditional mapping methods. They showed that shiver recovers missing sequence information and corrects inaccurately called bases, leading to a more complete and accurate reconstruction of the HIV genome. The tool has also been successfully applied to other viruses, including Hepatitis C Virus and Respiratory Syncytial Virus, showing Shiver's broad applicability.

The Future of HIV Research: Precision and Understanding

Shiver represents a significant step forward in HIV research, providing a more accurate and reliable method for reconstructing viral genomes. By overcoming the limitations of traditional mapping approaches, shiver opens new avenues for understanding HIV diversity, evolution, and transmission.

The ability to accurately reconstruct HIV genomes has far-reaching implications. It can improve our understanding of drug resistance, inform vaccine development, and enhance epidemiological studies. Ultimately, shiver has the potential to contribute to more effective prevention and treatment strategies for HIV.

As sequencing technologies continue to advance, tools like shiver will become increasingly important for unlocking the secrets of viral evolution and developing targeted interventions. Shiver is publicly available from https://github.com/ChrisHIV/shiver, empowering researchers worldwide to leverage its capabilities for their own studies.

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This article is based on research published under:

DOI-LINK: 10.1093/ve/vey007, Alternate LINK

Title: Easy And Accurate Reconstruction Of Whole Hiv Genomes From Short-Read Sequence Data With Shiver

Subject: Virology

Journal: Virus Evolution

Publisher: Oxford University Press (OUP)

Authors: Chris Wymant, François Blanquart, Tanya Golubchik, Astrid Gall, Margreet Bakker, Daniela Bezemer, Nicholas J Croucher, Matthew Hall, Mariska Hillebregt, Swee Hoe Ong, Oliver Ratmann, Jan Albert, Norbert Bannert, Jacques Fellay, Katrien Fransen, Annabelle Gourlay, M Kate Grabowski, Barbara Gunsenheimer-Bartmeyer, Huldrych F Günthard, Pia Kivelä, Roger Kouyos, Oliver Laeyendecker, Kirsi Liitsola, Laurence Meyer, Kholoud Porter, Matti Ristola, Ard Van Sighem, Ben Berkhout, Marion Cornelissen, Paul Kellam, Peter Reiss, Christophe Fraser

Published: 2018-01-01

Everything You Need To Know

What is 'shiver' and how does it aid in HIV research?

Shiver is a tool developed to accurately reconstruct entire HIV genomes from short sequences. It addresses the challenges posed by high diversity, frequent insertions, and deletions (indels) in HIV genetic data, which often hinder accurate analysis using standard methods. Shiver enhances our capacity to study HIV diversity and evolution, potentially leading to new treatments and prevention strategies.

Why is next-generation sequencing (NGS) not always sufficient for HIV research, and how does Shiver improve upon it?

Next-generation sequencing (NGS) can generate a high throughput and detailed analysis of minority variants, but it has limitations in HIV research due to the difficulty of accurately reconstructing the consensus sequence of a quasispecies. The high diversity and frequent indels present in HIV samples complicate the process, leading to inaccurate results. Shiver overcomes these limitations by pre-processing reads, removing contamination, and mapping them to a customized reference genome, which minimizes bias and maximizes accuracy.

How does Shiver's approach to creating a reference genome differ from traditional methods, and why is this significant?

Shiver creates a customized reference genome for each sample by assembling reads into contigs, correcting those contigs, and then filling gaps using the closest identified existing reference sequences. This contrasts with traditional methods that rely on mapping reads to a standard reference sequence, which can lead to biased data loss, especially in regions with high variability or indels. By tailoring the reference genome to the specific sample, Shiver minimizes mapping errors and ensures that even highly divergent reads are accurately aligned.

What specific steps does Shiver take to ensure accurate reconstruction of HIV genomes, and why are these steps important?

Shiver ensures accurate reconstruction through a multi-step process: Quality Control (thoroughly pre-processes reads), De Novo Assembly (aligns reads to create contigs), Contig Correction (corrects splicing and orientation), Customized Reference (builds a tailored reference genome), and Accurate Mapping (maps reads to the constructed reference). Each step is designed to minimize errors and maximize the accuracy of the final reconstructed genome. Without these steps, the reconstruction of the HIV genome would be of less accuracy.

Beyond HIV, what other applications does shiver have, and what are the implications for viral research?

Shiver not only improves HIV research but also demonstrates applicability to other viruses, such as Hepatitis C Virus and Respiratory Syncytial Virus. This suggests that the underlying principles of Shiver—customized reference genome construction and meticulous read processing—can be generalized to improve genomic analysis for a range of rapidly evolving viruses. Further research could explore extending Shiver to analyze other complex viral populations, improving our ability to understand and combat viral diseases more broadly.