ORCID Profile
0000-0002-9847-1526
Current Organisation
University of Oxford
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Publisher: Cold Spring Harbor Laboratory
Date: 07-10-2021
DOI: 10.1101/2021.10.04.21263560
Abstract: 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, and appears to have contributed to reduced rates of new infections. In iduals acting as sources of infection need to be characterised to design effective prevention strategies. We used viral genomes to investigate the demographic characteristics of sources of HIV-1 infection. Between 2014 and 2018, the HPTN 071 PopART study was conducted to quantify the public health benefits of ART. Viral s les from 7,124 study participants in Zambia were deep-sequenced as part of HPTN 071-02 PopART Phylogenetics, an ancillary study. We identified 300 likely HIV-1 transmission pairs and investigated the source in iduals in those pairs to better understand transmission in the general population. After demographic weighting, 59.4% of transmissions were male to female, with 43·2% (95% CI: 36·8%-49·7%) of transmissions being from males aged 25-40. Overall, men transmitted 2.09-fold (2·06-2·29) more infections per capita than women, a ratio peaking, when stratified by source age, at 5.88 (2·78-15·8) in the 35-39 age group. 17·4% of sources (12·5%-22·4%) carried viruses resistant to first-line ART. 12·9% (8·5%-17·3%) of transmissions linked in iduals from different communities in the trial. HIV-1 transmission in the HPTN 071 study communities comes from a wide range of age and sex groups, and that there is no outsized contribution of importation or drug resistance mutations to new infections. Men aged 25-40, under-served by current treatment and prevention service, should be prioritised for HIV testing and ART. National Institute of Allergy and Infectious Diseases, US President’s Emergency Plan for AIDS Relief, International Initiative for Impact Evaluation, Bill & Melinda Gates Foundation, National Institute on Drug Abuse, and National Institute of Mental Health We searched PubMed, with no date or language filters, to identify previous quantitative studies investigating the role of age, sex, mobility and drug resistance mutations (separately or in combination) as drivers of new HIV transmissions in heterosexual transmission in sub-Saharan Africa. Observational studies were considered along with those using phylogenetic or mathematical modelling methodologies. In observational studies, having an older partner or a migrant partner is frequently identified as a risk factor for HIV acquisition, particularly in women, but this is a slightly separate question to the quantification of the overall frequency of these demographics amongst the sources of new infections. The most recent studies of drug resistance have shown an increasing prevalence, particularly in NNRTI resistance. The ability to use phylogenetics to investigate HIV transmission is reasonably recent, and the ability to use it to reconstruct who infected whom in transmission pairs is more recent still. One previous, influential study in South Africa posited a key role of men in their 30s in infecting very young women, and being themselves infected by women in their 30s, but that work did not use a methodology that was able to conclusively reconstruct direction of transmission. A more recent study in Botswana found similar age distributions for male and female sources of transmission, with the average in idual being in their late 30s or early 40s. However, these ages were recorded at the time of study enrolment and do not take into account the time from infection to s ling. The paper also showed that, in that setting, the majority of transmissions were between members of the same community. A number of other phylogenetic studies have been concerned with the very specific dynamics of HIV-1 in the fishing communities of Lake Victoria. No previous phylogenetics work to our knowledge has considered the distribution of drug resistance mutations in sources, and none considered the interaction between source characteristics. We were unable to find any previous mathematical modelling studies for which the characterisation of sources according to these variables was a major focus. Our methodology uses a phylogenetic approach to identify likely transmission pairs and the direction of transmission between their members. We find a total of 300 pairs, larger than any previous study. We demonstrate a novel and simple new approach to accounting for potential s ling bias. We also employ a methodology that allows us to estimate the ages of the in iduals involved at the time of transmission, rather than that of s ling, countering a key bias in previous approaches. Partly for this reason, our age profiles for sources peak at earlier ages than in previous work, with an average in the early 30s for male sources and mid-20s for females. We fail to confirm the existence of a “renewal cycle” of transmission involving a major contribution from women in older age groups. We also examine the contribution of outside-community transmission and drug resistant mutations, and, for the first time, show that these three characteristics (age/sex, migration, and drug resistance) operate on separate axes and do not cluster together. We use our results to calculate the relative contribution of male to female sources to transmission in age bands, finding that this grows to a peak in the 35-39 age group in which men are responsible for almost six times as many new infections per capita as women. The heterosexual HIV epidemic in sub-Saharan Africa appears to be maintained by transmissions from young women and slightly, but not dramatically, older men. The contributions of sources transmitting drug-resistant virus, or sources who reside outside a focal community, is not particularly large, and there is no disproportionate contribution from in iduals who share any combination of a high-risk age group, a residence outside the community, and drug-resistant virus. In generalised HIV epidemics, it is tempting to attempt to identify particular demographic groups, of relatively small sizes, for whom intensive targeting of prevention measures will have a major effect on transmission in the general population. The current state of the evidence suggests that this may not be possible, as the demographic profile of sources of transmission is not dissimilar to that of the general population. While it may be more difficult and resource-intensive to design universal interventions for the whole population, there may be no shortcuts.
Publisher: Springer Science and Business Media LLC
Date: 08-05-2019
DOI: 10.1038/S41598-019-43524-9
Abstract: Advancing interventions to tackle the huge global burden of hepatitis B virus (HBV) infection depends on improved insights into virus epidemiology, transmission, within-host ersity, drug resistance and pathogenesis, all of which can be advanced through the large-scale generation of full-length virus genome data. Here we describe advances to a protocol that exploits the circular HBV genome structure, using isothermal rolling-circle lification to enrich HBV DNA, generating concatemeric licons containing multiple successive copies of the same genome. We show that this product is suitable for Nanopore sequencing as single reads, as well as for generating short-read Illumina sequences. Nanopore reads can be used to implement a straightforward method for error correction that reduces the per-read error rate, by comparing multiple genome copies combined into a single concatemer and by analysing reads generated from plus and minus strands. With this approach, we can achieve an improved consensus sequencing accuracy of 99.7% and resolve intra-s le sequence variants to form whole-genome haplotypes. Thus while Illumina sequencing may still be the most accurate way to capture within-s le ersity, Nanopore data can contribute to an understanding of linkage between polymorphisms within in idual virions. The combination of isothermal lification and Nanopore sequencing also offers appealing potential to develop point-of-care tests for HBV, and for other viruses.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 04-02-2022
Abstract: We discovered a highly virulent variant of subtype-B HIV-1 in the Netherlands. One hundred nine in iduals with this variant had a 0.54 to 0.74 log
Publisher: F1000 Research Ltd
Date: 15-10-2015
DOI: 10.12688/F1000RESEARCH.7201.1
Abstract: The advent of a miniaturized DNA sequencing device with a high-throughput contextual sequencing capability embodies the next generation of large scale sequencing tools. The MinION™ Access Programme (MAP) was initiated by Oxford Nanopore Technologies™ in April 2014, giving public access to their USB-attached miniature sequencing device. The MinION Analysis and Reference Consortium (MARC) was formed by a subset of MAP participants, with the aim of evaluating and providing standard protocols and reference data to the community. Envisaged as a multi-phased project, this study provides the global community with the Phase 1 data from MARC, where the reproducibility of the performance of the MinION was evaluated at multiple sites. Five laboratories on two continents generated data using a control strain of Escherichia coli K-12, preparing and sequencing s les according to a revised ONT protocol. Here, we provide the details of the protocol used, along with a preliminary analysis of the characteristics of typical runs including the consistency, rate, volume and quality of data produced. Further analysis of the Phase 1 data presented here, and additional experiments in Phase 2 of E. coli from MARC are already underway to identify ways to improve and enhance MinION performance.
Publisher: Springer Science and Business Media LLC
Date: 07-10-2021
Publisher: The Royal Society
Date: 16-11-2022
Abstract: The raw material for viral evolution is provided by intra-host mutations occurring during replication, transcription or post-transcription. Replication and transcription of Coronaviridae 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. We explored for the first time the mutational spectrum of SARS-CoV-2 (sub)genomic and anti(sub)genomic RNA. We use a high-quality deep sequencing dataset produced using a quantitative strand-aware sequencing method, controlled for artefacts and sequencing errors, and scrutinized for accurate detection of within-host ersity. The nucleotide differences between negative- and positive-sense strand consensus vary between patients and do not show dependence on age or sex. Similarities and differences in mutational patterns between within-host minor variants on the two RNA strands suggested strand-specific mutations or editing by host deaminases and oxidative damage. We observe generally neutral and slight negative selection on the negative strand, contrasting with purifying selection in ORF1a, ORF1b and S genes of the positive strand of the genome.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 16-04-2021
Abstract: A year into the severe acute respiratory syndrome coronavirus 2 pandemic, we are experiencing waves of new variants emerging. Some of these variants have worrying functional implications, such as increased transmissibility or antibody treatment escape. Lythgoe et al. have undertaken in-depth sequencing of more than 1000 hospital patients' isolates to find out how the virus is mutating within in iduals. Overall, there seem to be consistent and reproducible patterns of within-host virus ersity. The authors observed only one or two variants in most s les, but a few carried many variants. Although the evidence indicates strong purifying selection, including in the spike protein responsible for viral entry, the authors also saw evidence for transmission clusters associated with households and other possible superspreader events. After transmission, most variants fizzled out, but occasionally some initiated ongoing transmission and wider dissemination. Science , this issue p. eabg0821
Publisher: Springer Science and Business Media LLC
Date: 26-08-2021
DOI: 10.1038/S41467-021-25265-4
Abstract: Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in young children globally, but little is known about within-host RSV ersity. Here, we characterised within-host RSV populations using deep-sequencing data from 319 nasopharyngeal swabs collected during 2017–2020. RSV-B had lower consensus ersity than RSV-A at the population level, while exhibiting greater within-host ersity. Two RSV-B consensus sequences had an amino acid alteration (K68N) in the fusion (F) protein, which has been associated with reduced susceptibility to nirsevimab (MEDI8897), a novel RSV monoclonal antibody under development. In addition, several minor variants were identified in the antigenic sites of the F protein, one of which may confer resistance to palivizumab, the only licensed RSV monoclonal antibody. The differences in within-host virus populations emphasise the importance of monitoring for vaccine efficacy and may help to explain the different prevalences of monoclonal antibody-escape mutants between the two subgroups.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Mariateresa de Cesare.