26 results found
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
Illingworth CJR, Raghwani J, Serwadda D, et al., A de novo approach to inferring within-host fitness effects during untreated HIV-1 infection
<jats:title>Abstract</jats:title><jats:p>In the absence of effective antiviral therapy, HIV-1 evolves in response to the within-host environment, of which the immune system is an important aspect. During the earliest stages of infection, this process of evolution is very rapid, driven by a small number of CTL escape mechanisms. As the infection progresses, immune escape variants evolve under reduced magnitudes of selection, while competition between an increasing number of polymorphic alleles (i.e., clonal interference) makes it difficult to quantify the magnitude of selection acting upon specific variant alleles. To tackle this complex problem, we developed a novel multi-locus inference method to evaluate the role of selection during the chronic stage of within-host infection. We applied this method to targeted sequence data from the p24 and gp41 regions of HIV-1 collected from 34 patients with long-term untreated HIV-1 infection. We identify a broad distribution of beneficial fitness effects during infection, with a small number of variants evolving under strong selection and very many variants evolving under weaker selection. The uniquely large number of infections analysed granted a previously unparalleled statistical power to identify loci at which selection could be inferred to act with statistical confidence. Our model makes no prior assumptions about the nature of alleles under selection, such that any synonymous or non-synonymous variant may be inferred to evolve under selection. However, the majority of variants inferred with confidence to be under selection were non-synonymous in nature, and in nearly all cases were associated with either CTL escape in p24 or neutralising antibody escape in gp41. Sites inferred to be under selection in multiple hosts have high within-host and between-host diversity albeit not all sites with high between-host diversity were inferred to be under selection at the within-host level. Our identification of sel
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