Publications by authors named "George MacIntyre-Cockett"

Background: Estimating the time since HIV infection (TSI) at population level is essential for tracking changes in the global HIV epidemic. Most methods for determining TSI give a binary classification of infections as recent or non-recent within a window of several months, and cannot assess the cumulative impact of an intervention.

Results: We developed a Random Forest Regression model, HIV-phyloTSI, which combines measures of within-host diversity and divergence to generate continuous TSI estimates directly from viral deep-sequencing data, with no need for additional variables.

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Recombination plays a pivotal role in generating within-host diversity and enabling HIV's evolutionary success, particularly in evading the host immune response. Despite this, the variability in recombination rates across different settings and the underlying factors that drive these differences remain poorly understood. In this study, we analysed a large dataset encompassing hundreds of untreated, longitudinally sampled infections using both whole-genome long-read and short-read sequencing datasets.

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Hepatitis B virus (HBV) whole genome sequencing (WGS) is currently limited as the DNA viral loads (VL) of many clinical samples are below the threshold required to generate full genomes using current sequencing methods. We developed two pan-genotypic viral enrichment methods, using probe-based capture and tiled amplicon PCR (HEP-TILE) for HBV WGS. We demonstrate using mock samples that both enrichment methods are pan-genotypic (genotypes A-J).

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Respiratory syncytial virus (RSV) is the leading cause of hospitalisation for respiratory infection in young children. RSV disease severity is known to be age-dependent and highest in young infants, but other correlates of severity, particularly the presence of additional respiratory pathogens, are less well understood. In this study, nasopharyngeal swabs were collected from two cohorts of RSV-positive infants <12 months in Spain, the UK, and the Netherlands during 2017-20.

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Article Synopsis
  • * Those with persistent infections were found to have over 50% higher odds of experiencing long COVID symptoms compared to those without persistent infections.
  • * The research reveals viral mutations associated with these persistent infections, suggesting ongoing viral evolution and potential impacts on treatment and vaccine effectiveness.
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Background: In the last decade, universally available antiretroviral therapy (ART) has led to greatly improved health and survival of people living with HIV in sub-Saharan Africa, but new infections continue to appear. The design of effective prevention strategies requires the demographic characterisation of individuals acting as sources of infection, which is the aim of this study.

Methods: Between 2014 and 2018, the HPTN 071 PopART study was conducted to quantify the public health benefits of ART.

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The Office for National Statistics Coronavirus (COVID-19) Infection Survey (ONS-CIS) is the largest surveillance study of SARS-CoV-2 positivity in the community, and collected data on the United Kingdom (UK) epidemic from April 2020 until March 2023 before being paused. Here, we report on the epidemiological and evolutionary dynamics of SARS-CoV-2 determined by analysing the sequenced samples collected by the ONS-CIS during this period. We observed a series of sweeps or partial sweeps, with each sweeping lineage having a distinct growth advantage compared to their predecessors, although this was also accompanied by a gradual fall in average viral burdens from June 2021 to March 2023.

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In this study, we evaluated the impact of viral variant, in addition to other variables, on within-host viral burden, by analysing cycle threshold (Ct) values derived from nose and throat swabs, collected as part of the UK COVID-19 Infection Survey. Because viral burden distributions determined from community survey data can be biased due to the impact of variant epidemiology on the time-since-infection of samples, we developed a method to explicitly adjust observed Ct value distributions to account for the expected bias. By analysing the adjusted Ct values using partial least squares regression, we found that among unvaccinated individuals with no known prior exposure, viral burden was 44% lower among Alpha variant infections, compared to those with the predecessor strain, B.

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The raw material for viral evolution is provided by intra-host mutations occurring during replication, transcription or post-transcription. Replication and transcription of proceed through the synthesis of negative-sense 'antigenomes' acting as templates for positive-sense genomic and subgenomic RNA. Hence, mutations in the genomes of SARS-CoV-2 and other coronaviruses can occur during (and after) the synthesis of either negative-sense or positive-sense RNA, with potentially distinct patterns and consequences.

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Article Synopsis
  • Tools to detect SARS-CoV-2 variants are crucial for public health and the development of vaccines and therapies.
  • A new allele-specific probe PCR (ASP-PCR) method was created to efficiently identify virus variants, especially in samples with low viral loads or poor RNA quality.
  • ASP-PCR demonstrated higher accuracy than next-generation sequencing (NGS) in certain conditions and yielded nearly identical results to NGS, making it a strong complementary method for screening SARS-CoV-2.
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  • A highly virulent variant of subtype-B HIV-1 was found in the Netherlands, showing a significant increase in viral load (3.5 to 5.5 times higher) and faster decline of CD4 cells in 109 individuals compared to 6604 infected with other strains.
  • Without treatment, younger individuals with this variant can expect to reach advanced HIV-CD4 counts below 350 cells/mm³ within about 9 months after diagnosis, leading to serious health impacts.
  • The variant likely originated from a mutation in the 1990s, exhibiting heightened transmissibility and a unique mechanism of virulence, rather than through genetic recombination.
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  • Human respiratory syncytial virus (RSV) causes significant lower respiratory infections in young children, yet its within-host diversity remains poorly understood.
  • Analysis of deep-sequencing data from 319 nasopharyngeal swabs showed that RSV-B has lower overall genetic diversity but greater variability within individual hosts compared to RSV-A.
  • Key mutations in the F protein of RSV-B may lead to resistance against emerging RSV treatments, highlighting the need to monitor these viral changes for effective vaccination strategies.
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  • Researchers analyzed 1,313 clinical samples from the UK to study the spread and variants of the SARS-CoV-2 virus during the pandemic.
  • They found that infections generally show low diversity within hosts when viral loads are high, and transmission involves a narrow bottleneck, meaning most variants don't persist after transmission.
  • The study indicates that while new transmission-enhancing or immune-escape variants emerge infrequently, those that do are likely to spread quickly if transmitted successfully.
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Viral genetic sequencing can be used to monitor the spread of HIV drug resistance, identify appropriate antiretroviral regimes, and characterize transmission dynamics. Despite decreasing costs, next-generation sequencing (NGS) is still prohibitively costly for routine use in generalized HIV epidemics in low- and middle-income countries. Here, we present veSEQ-HIV, a high-throughput, cost-effective NGS sequencing method and computational pipeline tailored specifically to HIV, which can be performed using leftover blood drawn for routine CD4 cell count testing.

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