31 results found
Caudill VR, Qin S, Winstead R, et al., 2019, CpG-creating Mutations are Costly in Many Human Viruses
<jats:title>Abstract</jats:title><jats:p>Mutations can occur throughout the virus genome and may be beneficial or deleterious. We are interested in mutations that yield a C next to a G, producing CpG sites. CpG sites are rare in eukaryotic and viral genomes. For the eukaryotes, it is thought that CpG sites are rare because they are prone to mutation when methylated. In viruses, we know less about why CpG sites are rare. A previous study in HIV suggested that CpG-creating transition mutations are more costly that similar non-CpG-creating mutations. To determine if this is the case in other viruses, we analyzed the allele frequencies of CpG-creating and non-CpG-creating mutations across various strains, subtypes, and genes of viruses using existing data obtained from Genbank, HIV Databases, and Virus Pathogen Resource. Our results suggest that CpG sites are costly for most viruses. By understanding the cost of CpG sites, we can obtain further insights into the evolution and adaptation of viruses.</jats:p>
Pike VL, Lythgoe KA, King KC, 2019, On the diverse and opposing effects of nutrition on pathogen virulence, PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, Vol: 286, ISSN: 0962-8452
Raghwani J, Wu C-H, Ho CKY, et al., 2019, High-Resolution Evolutionary Analysis of Within-Host Hepatitis C Virus Infection, JOURNAL OF INFECTIOUS DISEASES, Vol: 219, Pages: 1722-1729, ISSN: 0022-1899
Thompson RN, Wymant C, Spriggs RA, et al., 2019, Link between the numbers of particles and variants founding new HIV-1 infections depends on the timing of transmission, Virus Evolution, Vol: 5, ISSN: 2057-1577
Understanding which HIV-1 variants are most likely to be transmitted is important for vaccine design and predicting virus evolution. Since most infections are founded by single variants, it has been suggested that selection at transmission has a key role in governing which variants are transmitted. We show that the composition of the viral population within the donor at the time of transmission is also important. To support this argument, we developed a probabilistic model describing HIV-1 transmission in an untreated population, and parameterised the model using both within-host next generation sequencing data and population-level epidemiological data on heterosexual transmission. The most basic HIV-1 transmission models cannot explain simultaneously the low probability of transmission and the non-negligible proportion of infections founded by multiple variants. In our model, transmission can only occur when environmental conditions are appropriate (e.g. abrasions are present in the genital tract of the potential recipient), allowing these observations to be reconciled. As well as reproducing features of transmission in real populations, our model demonstrates that, contrary to expectation, there is not a simple link between the number of viral variants and the number of viral particles founding each new infection. These quantities depend on the timing of transmission, and infections can be founded with small numbers of variants yet large numbers of particles. Including selection, or a bias towards early transmission (e.g. due to treatment), acts to enhance this conclusion. In addition, we find that infections initiated by multiple variants are most likely to have derived from donors with intermediate set-point viral loads, and not from individuals with high set-point viral loads as might be expected. We therefore emphasise the importance of considering viral diversity in donors, and the timings of transmissions, when trying to discern the complex factors governing
Abdullah N, Kelly JT, Graham SC, et al., 2018, Structure-Guided Identification of a Nonhuman Morbillivirus with Zoonotic Potential, JOURNAL OF VIROLOGY, Vol: 92, ISSN: 0022-538X
Thompson RN, Wymant C, Spriggs RA, et al., 2018, Link between the numbers of particles and variants founding new HIV-1 infections depends on the timing of transmission
<jats:title>ABSTRACT</jats:title><jats:p>Understanding which HIV-1 variants are most likely to be transmitted is important for vaccine design and predicting virus evolution. Since most infections are founded by single variants, it has been suggested that selection at transmission has a key role in governing which variants are transmitted. We show that the composition of the viral population within the donor at the time of transmission is also important. To support this argument, we developed a probabilistic model describing HIV-1 transmission in an untreated population, and parameterised the model using both within-host next generation sequencing data and population-level epidemiological data on heterosexual transmission. The most basic HIV-1 transmission models cannot explain simultaneously the low probability of transmission and the non-negligible proportion of infections founded by multiple variants. In our model, transmission can only occur when environmental conditions are appropriate (e.g. abrasions are present in the genital tract of the potential recipient), allowing these observations to be reconciled. As well as reproducing features of transmission in real populations, our model demonstrates that, contrary to expectation, there is not a simple link between the number of viral variants and the number of viral particles founding each new infection. These quantities depend on the timing of transmission, and infections can be founded with small numbers of variants yet large numbers of particles. Including selection, or a bias towards early transmission (e.g. due to treatment) acts to enhance this conclusion. In addition, we find that infections initiated by multiple variants are most likely to have derived from donors with intermediate set-point viral loads, and not from individuals with high set-point viral loads as might be expected. We therefore emphasise the importance of considering viral diversity in donors, and the timings of transmiss
Raghwani J, Wu C-H, Ho CKY, et al., 2018, High resolution evolutionary analysis of within-host hepatitis C virus infection
<jats:title>ABSTRACT</jats:title><jats:p>Despite the breakthroughs in the treatment of HCV infection in recent years, we have a limited understanding of how virus diversity generated within individuals impacts the evolution and spread of HCV variants at the population scale. Addressing this gap will be important for building models for molecular epidemiology, which can identify main sources of disease transmission and evaluate the risks of drug-resistance mutations emerging and disseminating in a population. Here, we have undertaken a high-resolution analysis of HCV within-host evolution from four individuals co-infected with HIV. Specifically, we used long-read, deep-sequenced data of the full-length HCV envelope glycoprotein, longitudinally sampled from acute to chronic HCV infection to investigate the underlying viral evolutionary dynamics. In three individuals we found strong statistical support for population structure maintaining within-host HCV genetic diversity. Furthermore, we found significant variation in rates of molecular evolution among different regions of the HCV envelope region, both within and between individuals. Lastly, we report the first estimate of the within-host population genetic rate of recombination for HCV (0.28 x 10<jats:sup>-7</jats:sup> recombinations per site per day; interquartile range: 0.13-1.05 x 10<jats:sup>-7</jats:sup>), which is two orders of magnitude lower than that estimated for HIV-1, and four orders of magnitude lower than the nucleotide substitution rate of the HCV envelope gene. Together, these observations indicate that population structure and strong genetic linkage shapes within-host HCV evolutionary dynamics. These results will guide the future investigation of potential HCV drug resistance adaptation during infection, and at the population scale.</jats:p>
Lumley SF, McNaughton AL, Klenerman P, et al., 2018, Hepatitis B virus Adaptation to the CD8+T Cell Response: Consequences for Host and Pathogen, FRONTIERS IN IMMUNOLOGY, Vol: 9, ISSN: 1664-3224
Raghwani J, Redd AD, Longosz AF, et al., 2018, Evolution of HIV-1 within untreated individuals and at the population scale in Uganda, PLOS PATHOGENS, Vol: 14, ISSN: 1553-7366
Lythgoe KA, Gardner A, Pybus OG, et al., 2017, Short-sighted virus evolution and a germline hypothesis for chronic viral infections., Trends in Microbiology, Vol: 25, Pages: 336-348, ISSN: 0966-842X
With extremely short generation times and high mutability, many viruses can rapidly evolve and adapt to changing environments. This ability is generally beneficial to viruses as it allows them to evade host immune responses, evolve new behaviours, and exploit ecological niches. However, natural selection typically generates adaptation in response to the immediate selection pressures that a virus experiences in its current host. Consequently, we argue that some viruses, particularly those characterised by long durations of infection and ongoing replication, may be susceptible to short-sighted evolution, whereby a virus' adaptation to its current host will be detrimental to its onward transmission within the host population. Here we outline the concept of short-sighted viral evolution and provide examples of how it may negatively impact viral transmission among hosts. We also propose that viruses that are vulnerable to short-sighted evolution may exhibit strategies that minimise its effects. We speculate on the various mechanisms by which this may be achieved, including viral life history strategies that result in low rates of within-host evolution, or the establishment of a 'germline' lineage of viruses that avoids short-sighted evolution. These concepts provide a new perspective on the way in which some viruses have been able to establish and maintain global pandemics.
Doekes HM, Fraser C, Lythgoe KA, 2017, Effect of the latent reservoir on the evolution of HIV at the within- and between-host Levels, PLoS Computational Biology, Vol: 13, Pages: 1-27, ISSN: 1553-734X
The existence of long-lived reservoirs of latently infected CD4+ T cells is the major barrier to curing HIV, and has been extensively studied in this light. However, the effect of these reservoirs on the evolutionary dynamics of the virus has received little attention. Here, we present a within-host quasispecies model that incorporates a long-lived reservoir, which we then nest into an epidemiological model of HIV dynamics. For biologically plausible parameter values, we find that the presence of a latent reservoir can severely delay evolutionary dynamics within a single host, with longer delays associated with larger relative reservoir sizes and/or homeostatic proliferation of cells within the reservoir. These delays can fundamentally change the dynamics of the virus at the epidemiological scale. In particular, the delay in within-host evolutionary dynamics can be sufficient for the virus to evolve intermediate viral loads consistent with maximising transmission, as is observed, and not the very high viral loads that previous models have predicted, an effect that can be further enhanced if viruses similar to those that initiate infection are preferentially transmitted. These results depend strongly on within-host characteristics such as the relative reservoir size, with the evolution of intermediate viral loads observed only when the within-host dynamics are sufficiently delayed. In conclusion, we argue that the latent reservoir has important, and hitherto under-appreciated, roles in both within- and between-host viral evolution.
Blanquart F, Grabowski MK, Herbeck J, et al., 2016, A transmission-virulence evolutionary trade-off explains attenuation of HIV-1 in Uganda, eLife, Vol: 5, ISSN: 2050-084X
Evolutionary theory hypothesizes that intermediate virulence maximizes pathogenfitness as a result of a trade-off between virulence and transmission, but empirical evidenceremains scarce. We bridge this gap using data from a large and long-standing HIV-1 prospectivecohort, in Uganda. We use an epidemiological-evolutionary model parameterised with this data toderive evolutionary predictions based on analysis and detailed individual-based simulations. Werobustly predict stabilising selection towards a low level of virulence, and rapid attenuation of thevirus. Accordingly, set-point viral load, the most common measure of virulence, has declined in thelast 20 years. Our model also predicts that subtype A is slowly outcompeting subtype D, with bothsubtypes becoming less virulent, as observed in the data. Reduction of set-point viral loads shouldhave resulted in a 20% reduction in incidence, and a three years extension of untreatedasymptomatic infection, increasing opportunities for timely treatment of infected individuals.
Lythgoe KA, Blanquart F, Pellis L, et al., 2016, Large Variations in HIV-1 Viral Load Explained by Shifting-Mosaic Metapopulation Dynamics, PLOS Biology, Vol: 14, ISSN: 1545-7885
The viral population of HIV-1, like many pathogens that cause systemic infection, is structured and differentiated within the body. The dynamics of cellular immune trafficking through the blood and within compartments of the body has also received wide attention. Despite these advances, mathematical models, which are widely used to interpret and predict viral and immune dynamics in infection, typically treat the infected host as a well-mixed homogeneous environment. Here, we present mathematical, analytical, and computational results that demonstrate that consideration of the spatial structure of the viral population within the host radically alters predictions of previous models. We study the dynamics of virus replication and cytotoxic T lymphocytes (CTLs) within a metapopulation of spatially segregated patches, representing T cell areas connected by circulating blood and lymph. The dynamics of the system depend critically on the interaction between CTLs and infected cells at the within-patch level. We show that for a wide range of parameters, the system admits an unexpected outcome called the shifting-mosaic steady state. In this state, the whole body's viral population is stable over time, but the equilibrium results from an underlying, highly dynamic process of local infection and clearance within T-cell centers. Notably, and in contrast to previous models, this new model can explain the large differences in set-point viral load (SPVL) observed between patients and their distribution, as well as the relatively low proportion of cells infected at any one time, and alters the predicted determinants of viral load variation.
Fraser C, Lythgoe K, Leventhal GE, et al., 2014, Virulence and Pathogenesis of HIV-1 Infection: An Evolutionary Perspective, SCIENCE, Vol: 343, Pages: 1328-+, ISSN: 0036-8075
van de Vijver DA, Nichols BE, Abbas UL, et al., 2013, Pre-exposure prophylaxis (PrEP) will have a limited impact on the prevalence of HIV-1 drug resistance in sub-Saharan Africa: comparison of mathematical models, AIDS, Vol: 27, Pages: 2943-2951, ISSN: 0269-9370
BACKGROUND: Preexposure prophylaxis (PrEP) with tenofovir and emtricitabine can prevent new HIV-1 infections, but there is a concern that use of PrEP could increase HIV drug resistance resulting in loss of treatment options. We compared standardized outcomes from three independent mathematical models simulating the impact of PrEP on HIV transmission and drug resistance in sub-Saharan African countries.METHODS: All models assume that people using PrEP receive an HIV test every 3-6 months. The models vary in structure and parameter choices for PrEP coverage, effectiveness of PrEP (at different adherence levels) and the rate with which HIV drug resistance emerges and is transmitted.RESULTS: The models predict that the use of PrEP in conjunction with antiretroviral therapy will result in a lower prevalence of HIV than when only antiretroviral therapy is used. With or without PrEP, all models suggest that HIV drug resistance will increase over the next 20 years due to antiretroviral therapy. PrEP will increase the absolute prevalence of drug resistance in the total population by less than 0.5% and amongst infected individuals by at most 7%. Twenty years after the introduction of PrEP, the majority of drug-resistant infections is due to antiretroviral therapy (50-63% across models), whereas 40-50% will be due to transmission of drug resistance, and less than 4% to the use of PrEP.CONCLUSION: HIV drug resistance resulting from antiretroviral therapy is predicted to far exceed that resulting from PrEP. Concern over drug resistance should not be a reason to limit the use of PrEP.
van de Vijver DAMC, Nichols BE, Abbas UL, et al., 2013, Preexposure prophylaxis will have a limited impact on HIV-1 drug resistance in sub-Saharan Africa: a comparison of mathematical models, AIDS, Vol: 27, Pages: 2943-2951, ISSN: 0269-9370
Lythgoe KA, Pellis L, Fraser C, 2013, IS HIV SHORT-SIGHTED? INSIGHTS FROM A MULTISTRAIN NESTED MODEL, EVOLUTION, Vol: 67, Pages: 2769-2782, ISSN: 0014-3820
Lythgoe K, 2013, Invisible foes, Current Biology, Vol: 23, Pages: R548-R549, ISSN: 0960-9822
Lythgoe KA, Fraser C, 2012, New insights into the evolutionary rate of HIV-1 at the within-host and epidemiological levels, PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, Vol: 279, Pages: 3367-3375, ISSN: 0962-8452
Lythgoe KA, Morrison LJ, Read AF, et al., 2007, Parasite-intrinsic factors can explain ordered progression of trypanosome antigenic variation, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 104, Pages: 8095-8100, ISSN: 0027-8424
Barry JD, Marcello L, Morrison LJ, et al., 2005, What the genome sequence is revealing about trypanosome antigenic variation, BIOCHEMICAL SOCIETY TRANSACTIONS, Vol: 33, Pages: 986-989, ISSN: 0300-5127
Lythgoe KA, Chao L, 2003, Mechanisms of coexistence of a bacteria and a bacteriophage in a spatially homogeneous environment, ECOLOGY LETTERS, Vol: 6, Pages: 326-334, ISSN: 1461-023X
Lythgoe KA, 2002, Effects of acquired immunity and mating strategy on the genetic structure of parasite populations, AMERICAN NATURALIST, Vol: 159, Pages: 519-529, ISSN: 0003-0147
Lythgoe KA, 2000, The coevolution of parasites with host-acquired immunity and the evolution of sex, EVOLUTION, Vol: 54, Pages: 1142-1156, ISSN: 0014-3820
Lythgoe KA, Read AF, 1998, Catching the Red Queen? The advice of the rose, TRENDS IN ECOLOGY & EVOLUTION, Vol: 13, Pages: 473-474, ISSN: 0169-5347
Lythgoe KA, 1997, Consequences of gene flow in spatially structured populations, GENETICS RESEARCH, Vol: 69, Pages: 49-60, ISSN: 0016-6723
Fryer HR, Raghwani J, Gill MJ, et al., Limited evolution despite years of measurable viremia in a cART-treated seronegative HIV-1 positive individual
<jats:title>Abstract</jats:title><jats:p>Understanding the role that antibodies play in controlling HIV-1 infection and in the dynamics that underpin the formation of the HIV-1 reservoir are important steps towards combatting this global disease. To address these gaps, we performed whole-genome, deep sequence analysis of longitudinal plasma HIV-1 samples from an individual who failed to develop detectable anti-HIV-1 antibodies for 4 years post infection. These analyses reveal limited evolution despite months of measurable viremia during treatment with cART. We used a mathematical model to simultaneously analyse the viral and evolutionary dynamics of this unique individual. We propose a role for antibodies in reducing viral infectivity and demonstrate how our data are consistent with a theory of rapid activation of latently infected cells prior to effective viral suppression. Our study supports and elucidates a recent finding that although the latent reservoir persists for years once virus is effectively suppressed, prior to suppression, viral strains within the reservoir turn over rapidly. The implications for a cure are significant.</jats:p>
Lythgoe KA, Lumley SF, McKeating JA, et al., Estimation of hepatitis B virus cccDNA persistence in chronic infection using within-host evolutionary rates
<jats:p>Hepatitis B virus (HBV) infection is a major global health problem with over 240 million infected individuals at risk of developing progressive liver disease and hepatocellular carcinoma. HBV is an enveloped DNA virus that establishes its genome as an episomal, covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. Currently available standard-of-care treatments for chronic hepatitis B (CHB) include nucleos(t)ide analogues (NA) that suppress HBV replication but do not target the cccDNA and hence rarely cure infection. There is considerable interest in determining the lifespan of cccDNA molecules to design and evaluate new curative treatments. We took a novel approach to this problem by developing a new mathematical framework to model changes in evolutionary rates during infection which, combined with previously determined within-host evolutionary rates of HBV, we used to determine the lifespan of cccDNA. We estimate that during HBe-antigen positive (HBeAgPOS) infection the cccDNA lifespan is 61 (36-236) days, whereas during the HBeAgNEG phase of infection it is only 26 (16-81) days. We found that cccDNA replicative capacity declined by an order of magnitude between HBeAgPOS and HBeAgNEG phases of infection. Our estimated lifespan of cccDNA is too short to explain the long durations of chronic infection observed in patients on NA treatment, suggesting that either a sub-population of long-lived hepatocytes harbouring cccDNA molecules persists during therapy, or that NA therapy does not suppress all viral replication. These results provide a greater understanding of the biology of the cccDNA reservoir and can aid the development of new curative therapeutic strategies for treating CHB.</jats:p>
<jats:p>Hepatitis B virus (HBV) DNA viral loads (VL) show wide variation between individuals with chronic hepatitis B (CHB) infection, and are used to determine treatment eligibility. There are few refined descriptions of VL distribution in CHB, and limited understanding of the biology that underpins these patterns. We set out to describe the VL distribution in independent cohorts from the UK and South Africa, to identify associated host characteristics, and to compare with VL in HIV-1 and hepatitis C (HCV) infection. We show the presence of a set-point in chronic HBV infection and report significant differences in the viral load distribution of HBV when compared to HIV and HCV.</jats:p>
Villabona-Arenas CJ, Hall M, Lythgoe KA, et al., HIV-1 founder variant multiplicity is determined by the infection stage of the source partner
<jats:p>During sexual transmission, the large genetic diversity of HIV-1 within an individual is frequently reduced to one founder variant that initiates infection. Understanding the drivers of this bottleneck is crucial to develop effective infection control strategies. Genetic characteristics of the potential founder viruses and events in the recipient partner are both known to contribute to this bottleneck, but little is understood about the importance of the source partner. To test the hypothesis that the source partner affects the multiplicity of HIV founder variants, we developed a phylodynamic model calibrated using genetic and epidemiological data on all existing transmission pairs for whom the direction of transmission and the infection stage of the source partner are known. Our results demonstrate the importance of infection stage of the source partner, and not exposure route, in determining founder variant multiplicity. Specifically, acquiring infection from someone in the acute (early) stage of infection increases the risk of multiple variant transmission when compared with someone in the chronic (later) stage of infection. This study provides the first direct test of source partner characteristics to explain the low frequency of multiple founder strain infections and can inform clinical intervention study design and interpretation.</jats:p>
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