Biology subjects

Beloukas, A.

Publications and source records attributed to Beloukas, A..

3 recordsLinked to original sources

bioRxiv2023

A detailed characterisation of drug resistance during darunavir/ritonavir (DRV/r) monotherapy highlights a high barrier to the emergence of resistance mutations in protease but identifies alternative pathways of resistance

BackgroundMaintenance monotherapy with DRV/r has yielded variable outcomes and is not recommended. Trial samples offer valuable opportunities for detailed studies. We analysed samples from a 48-week trial in Cameroon to obtain a detailed characterisation of drug resistance. MethodsFollowing failure of NNRTI-based therapy and virological suppression on PI-based therapy, participants were assigned to receive either DRV/r (n=81) or TDF/3TC + LPV/r (n=39). PBMC from study entry underwent bulk protease and RT sequencing. Plasma collected at virological rebound (confirmed or last available HIV-1 RNA >60 copies/ml) underwent ultradeep protease and RT sequencing and bulk gag-protease sequencing. A site-directed mutant with T375A (p2/p7) was phenotypically characterised using a single-cycle assay. ResultsHIV-1 DNA analysis revealed NRTI and NNRTI resistance-associated mutations (RAMs) in 52/90 (57.8%) and 53/90 (58.9%) samples, respectively. In rebound HIV-1 RNA (DRV/r n=21; LPV/r n=2), prevalence was 9/23 (39.1%) and 10/23 (43.5%), respectively, with most RAMs occurring at frequencies [≥]15%. No DRV RAMs were found. Paired HIV-1 DNA and RNA sequences showed partial consistency in resistance patterns. Among 8 participants experiencing virological rebound on DRV/r (n=12 samples), all showed gag mutations associated with PI-exposure, including T375N, T375A (p2/p7), K436R (p7/p1), and mutations in p17, p24, p2 and p6. T375A conferred 10-fold DRV resistance and increased replication capacity. ConclusionsThe study highlights the high resistance barrier of DRV/r while identifying alternative pathways of DRV resistance through gag substitutions. During virological suppression, resistance patterns in HIV-1 DNA reflect treatment history, but due to technical and biological considerations, cautious interpretation is warranted.

microbiology↗

bioRxiv2020

Population genomics insights into the recent evolution of SARS-CoV-2

The current coronavirus disease 2019 (COVID-19) pandemic is caused by the SARS-CoV-2 virus and is still spreading rapidly worldwide. Full-genome-sequence computational analysis of the SARS-CoV-2 genome will allow us to understand the recent evolutionary events and adaptability mechanisms more accurately, as there is still neither effective therapeutic nor prophylactic strategy. In this study, we used population genetics analysis to infer the mutation rate and plausible recombination events that may have contributed to the evolution of the SARS-CoV-2 virus. Furthermore, we localized targets of recent and strong positive selection. The genomic regions that appear to be under positive selection are largely co-localized with regions in which recombination from non-human hosts appeared to have taken place in the past. Our results suggest that the pangolin coronavirus genome may have contributed to the SARS-CoV-2 genome by recombination with the bat coronavirus genome. However, we find evidence for additional recombination events that involve coronavirus genomes from other hosts, i.e., Hedgehog and Sparrow. Even though recombination events within human hosts cannot be directly assessed, due to the high similarity of SARS-CoV-2 genomes, we infer that recombinations may have recently occurred within human hosts using a linkage disequilibrium analysis. In addition, we employed an Approximate Bayesian Computation approach to estimate the parameters of a demographic scenario involving an exponential growth of the size of the SARS-CoV-2 populations that have infected European, Asian and Northern American cohorts, and we demonstrated that a rapid exponential growth in population size can support the observed polymorphism patterns in SARS-CoV-2 genomes.

evolutionary biology↗

bioRxiv2018

A systematic review of Hepatitis B virus (HBV) drug and vaccine escape mutations in Africa: a call for urgent action

International sustainable development goals for the elimination of viral hepatitis as a public health problem by 2030 highlight the pressing need to optimize strategies for prevention, diagnosis and treatment. Selected or transmitted resistance associated mutations (RAMs) and vaccine escape mutations (VEMs) in hepatitis B virus (HBV) may reduce the success of existing treatment and prevention strategies. These issues are particularly pertinent for many settings in Africa where there is high HBV prevalence and co-endemic HIV infection, but lack of robust epidemiological data and limited education, diagnostics and clinical care. The prevalence, distribution and impact of RAMs and VEMs in these populations are neglected in the current literature. We therefore set out to assimilate data for sub-Saharan Africa through a systematic literature review and analysis of published sequence data, and present these in an on-line database (https://livedataoxford.shinyapps.io/1510659619-3Xkoe2NKkKJ7Drg/). The majority of the data were from HIV/HBV coinfected cohorts. The commonest RAM was rtM204I/V, either alone or in combination with compensatory mutations, and identified in both reportedly treatment-naive and treatment-experienced adults. We also identified the suite of mutations rtM204V/I + rtL180M + rtV173L, that has been associated with vaccine escape, in over 1/3 of cohorts. Although tenofovir has a high genetic barrier to resistance, it is of concern that emerging data suggest polymorphisms that may be associated with resistance, although the precise clinical impact of these is unknown. Overall, there is an urgent need for improved diagnostic screening, enhanced laboratory assessment of HBV before and during therapy, and sustained roll out of tenofovir in preference to lamivudine alone. Further data are needed in order to inform population and individual approaches to HBV diagnosis, monitoring and therapy in these highly vulnerable settings.\n\nAuthors summaryThe Global Hepatitis Health Sector Strategy is aiming for the elimination of viral hepatitis as a public health threat by 2030. However, mutations associated with drug resistance and vaccine escape may reduce the success of existing treatment and prevention strategies. In the current literature, the prevalence, distribution and impact of hepatitis B virus (HBV) mutations in many settings in Africa are neglected, despite the high prevalence of HBV and co-endemic HIV infection. This systematic review describes the frequency, prevalence and co-occurrence of mutations associated with HBV drug resistance and vaccine escape mutations in Africa. The findings suggest a high prevalence of these mutations in some populations in sub-Saharan Africa. Scarce resources have contributed to the lack of HBV diagnostic screening, inconsistent supply of drugs, and poor access to clinical monitoring, all of which contribute to drug and vaccine resistance. Sustainable long-term investment is required to expand consistent drug and vaccine supply, to provide screening to diagnose infection and to detect drug resistance, and to provide appropriate targeted clinical monitoring for treated patients.

epidemiology↗