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A new variant of SARS-CoV-2 has emerged which is increasing in frequency, primarily in the South East of England (lineage B.1.1.7 (1); VUI-202012/01). One potential hypothesis is that infection with the new variant results in higher viral loads, which in turn may make the virus more transmissible. We found higher (sequence derived) viral loads in samples from individuals infected with the new variant with median inferred viral loads were three-fold higher in individuals with the new variant. Most of the new variants were sampled in Kent and Greater London. We observed higher viral loads in Kent compared to Greater London for both the new variant and other circulating lineages. Outside Greater London, the variant has higher viral loads, whereas within Greater London, the new variant does not have significantly higher viral loads compared to other circulating lineages. Higher variant viral loads outside Greater London could be due to demographic effects, such as a faster variant growth rate compared to other lineages or concentration in particular age-groups. However, our analysis does not exclude a causal link between infection with the new variant and higher viral loads. This is a preliminary analysis and further work is needed to investigate any potential causal link between infection with this new variant and higher viral loads, and whether this results in higher transmissibility, severity of infection, or affects relative rates of symptomatic and asymptomatic infectionDocument Description and PurposeThis is an updated report submitted to NERVTAG in December 2020 as part of urgent investigations into the new variant of SARS-COV-2 (VUI-202012/01). It makes full use of (and is restricted to) all sequence data and associated metadata available to us at the time this original report was submitted and remains provisional. Under normal circumstances more genomes and metadata would be obtained and included before making this report public. We will update this preprint when more genomes and metadata are available and before submitting for peer review.

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.

Although antiretroviral drug therapy suppresses human immunodeficiency virus-type 1 (HIV-1) to undetectable levels in the blood of treated individuals, reservoirs of replication competent HIV-1 endure. Upon cessation of antiretroviral therapy, the reservoir usually allows outgrowth of virus and approaches to targeting the reservoir have had limited success. Ongoing cycles of viral replication in regions with low drug penetration contribute to this persistence. Here, we use a mathematical model to illustrate a new approach to eliminating the part of the reservoir attributable to persistent replication in drug sanctuaries. Reducing the residency time of CD4 T cells in drug sanctuaries renders ongoing replication unsustainable in those sanctuaries. We hypothesize that, in combination with antiretroviral drugs, a strategy to orchestrate CD4 T cell trafficking could contribute to a functional cure for HIV-1 infection., Author summary Despite the success of potent antiretroviral therapy in suppressing the amount of virus in peripheral blood for long periods of time, a reservoir of infectious virus persists in CD4 T cells, implying the need for long-term treatment. Strategies to control and ultimately eliminate the viral reservoir within specific tissue compartments will need to target virus that persists in both a long-lived reservoir of infectious virus in CD4 T cells as well as low-levels of viral replication that continues despite antiretroviral drug therapy. Using a mathematical model, we describe a hypothetical new therapeutic approach to eliminating HIV-1 persistence in these ‘drug sanctuaries’. Specifically, we show that therapy that increases the rate that the target cells for HIV-1 flow through drug sanctuaries could stop continuous cycles of replication. Used in combination with antiretroviral treatment, such a therapy could contribute to a functional cure for HIV-1.

Objective:\ud This article predicts the future epidemiology of HIV-2 in Caió, a rural region of Guinea Bissau; and investigates whether HIV-2, which has halved in prevalence between 1990 and 2007 and is now almost absent in young adults in Caió, can persist as an infection of the elderly.\ud Design:\ud A mathematical model of the spread of HIV-2 was tailored to the epidemic in Caió, a village in Guinea-Bissau.\ud Methods:\ud An age-stratified difference equation model of HIV-2 transmission was fitted to age-stratified HIV-2 incidence and prevalence data from surveys conducted in Caió in 1990, 1997 and 2007. A stochastic version of the same model was used to make projections.\ud Results:\ud HIV-2 infection is predicted to continue to rapidly decline in Caió such that new infections will cease and prevalence will reach low levels (e.g. below 0.1%) within a few decades. HIV-2 is not predicted to persist in the elderly.\ud Conclusion:\ud HIV-2 is predicted go extinct in Caió during the second half of this century.

Understanding the circumstances under which exposure to transmissible spongiform encephalopathies (TSEs) leads to infection is important for managing risks to public health. Based upon ideas in toxicology and radiology, it is plausible that exposure to harmful agents, including TSEs, is completely safe if the dose is low enough. However, the existence of a threshold, below which infection probability is zero has never been demonstrated experimentally. Here we explore this question by combining data and mathematical models that describe scrapie infections in mice following experimental challenge over a broad range of doses. We analyse data from 4338 mice inoculated at doses ranging over ten orders of magnitude. These data are compared to results from a within-host model in which prions accumulate according to a stochastic birth-death process. Crucially, this model assumes no threshold on the dose required for infection. Our data reveal that infection is possible at the very low dose of a 1000 fold dilution of the dose that infects half the challenged animals (ID50). Furthermore, the dose response curve closely matches that predicted by the model. These findings imply that there is no safe dose of prions and that assessments of the risk from low dose exposure are right to assume a linear relationship between dose and probability of infection. We also refine two common perceptions about TSE incubation periods: that their mean values decrease linearly with logarithmic decreases in dose and that they are highly reproducible between hosts. The model and data both show that the linear decrease in incubation period holds only for doses above the ID50. Furthermore, variability in incubation periods is greater than predicted by the model, not smaller. This result poses new questions about the sources of variability in prion incubation periods. It also provides insight into the limitations of the incubation period assay.

Lymphoid tissue is a key reservoir established by HIV-1 during acute infection. It is a site associated with viral production, storage of viral particles in immune complexes, and viral persistence. Although combinations of antiretroviral drugs usually suppress viral replication and reduce viral RNA to undetectable levels in blood, it is unclear whether treatment fully suppresses viral replication in lymphoid tissue reservoirs. Here we show that virus evolution and trafficking between tissue compartments continues in patients with undetectable levels of virus in their bloodstream. We present a spatial and dynamic model of persistent viral replication and spread that indicates why the development of drug resistance is not a foregone conclusion under conditions in which drug concentrations are insufficient to completely block virus replication. These data provide new insights into the evolutionary and infection dynamics of the virus population within the host, revealing that HIV-1 can continue to replicate and replenish the viral reservoir despite potent antiretroviral therapy.

Scrapie control in Great Britain (GB) was originally based on the National Scrapie Plan's Ram Genotyping scheme aimed at reducing the susceptibility of the national flock. The current official strategy to control scrapie in the national flock involves culling susceptible genotypes in individual, known affected flocks (compulsory scrapie flock scheme or CSFS). However, the recent development of preclinical test candidates means that a strategy based on disease detection may now be feasible. Here, a deterministic within-flock model was used to demonstrate that only large flocks with many home-bred ewes are likely to be a significant risk for flock-to-flock transmission of scrapie. For most other flocks, it was found that the CSFS could be replaced by a strategy using a currently available live test without excessive risk to other farmers, even if the proportion of susceptible genotypes in the flock is unusually large. Even for flocks that represent a high risk of harbouring a high prevalence of infection, there would be limited probability of onward transmission if scrapie is detected soon after disease introduction (typically less than 5 years). However, if detection of disease is delayed, the existing CSFS strategy may be the most appropriate control measure in these cases.

Identifying human immunodeficiency virus (HIV) immune escape mutations has implications for understanding the impact of host immunity on pathogen evolution and guiding the choice of vaccine antigens. One means of identifying cytotoxic-T-lymphocyte (CTL) escape mutations is to search for statistical associations between mutations and host human leukocyte antigen (HLA) class I alleles at the population level. The impact of evolutionary rates on the strength of such associations is not well defined. Here, we address this topic using a mathematical model of within-host evolution and between-host transmission of CTL escape mutants that predicts the prevalence of escape mutants at the population level. We ask how the rates at which an escape mutation emerges in a host who bears the restricting HLA and reverts when transmitted to a host who does not bear the HLA affect the strength of an association. We consider the impact of these factors when using a standard statistical method to test for an association and when using an adaptation of that method that corrects for phylogenetic relationships. We show that with both methods, the average sample size required to identify an escape mutation is smaller if the mutation escapes and reverts quickly. Thus, escape mutations identified as HLA associated systematically favor those that escape and revert rapidly. We also present expressions that can be used to infer escape and reversion rates from cross-sectional escape prevalence data.

Cost-benefit is rarely combined with nonlinear dynamic models when evaluating control options for infectious diseases. The current strategy for scrapie in Great Britain requires that all genetically susceptible livestock in affected flocks be culled (Compulsory Scrapie Flock Scheme or CSFS). However, this results in the removal of many healthy sheep, and a recently developed pre-clinical test for scrapie now offers a strategy based on disease detection. We explore the flock level cost-effectiveness of scrapie control using a deterministic transmission model and industry estimates of costs associated with genotype testing, pre-clinical tests and the value of a sheep culled. Benefit was measured in terms of the reduction in the number of infected sheep sold on, compared to a baseline strategy of doing nothing, using Incremental Cost Effectiveness analysis to compare across strategies. As market data was not available for pre-clinical testing, a threshold analysis was used to set a unit-cost giving equal costs for CSFS and multiple pre-clinical testing (MT, one test each year for three consecutive years). Assuming a 40% within-flock proportion of susceptible genotypes and a test sensitivity of 90%, a single test (ST) was cheaper but less effective than either the CSFS or MT strategies (30 infected-sales-averted over the lifetime of the average epidemic). The MT strategy was slightly less effective than the CSFS and would be a dominated strategy unless preclinical testing was cheaper than the threshold price of £6.28, but may be appropriate for flocks with particularly valuable livestock. Though the ST is not currently recommended, the proportion of susceptible genotypes in the national flock is likely to continue to decrease; this may eventually make it a cost-effective alternative to the MT or CSFS.

The first antiretroviral therapy (ARV) drug, azidothymidine (zidovudine, originally developed to treat cancer), was discovered to inhibit the reverse transcriptase (RT) enzyme of HIV in 1986 (Yarchoan, et al. 1986). Since then, more inhibitor classes to other essential steps of viral replication have been discovered (Barbaro, et al. 2005). The ability of HIV to mutate and recombine frequently allows it to evade individual ARV rapidly (Aboulker and Swart 1993). In 1996, the introduction of combination ARV, often termed highly active antiretroviral therapy (HAART), introduced a dramatic treatment response to patients. HAART delays disease progression, reduces AIDS mortality (by up to 70% annually) and partially restores CD4 T cells, but cannot clear HIV infection (Palella, et al. 1998). Furthermore, HAART delays the emergence of resistant HIV isolates, which accumulated rapidly during the pre-HAART era, when mono-, or dual-, therapy were in use (Kuritzkes 2007).

Because cytotoxic T-lymphocytes (CTLs) have been shown to play a role in controlling human immunodeficiency virus (HIV) infection and because CTL-based simian immunodeficiency virus (SIV) vaccines have proved effective in non-human primates, one goal of HIV vaccine design is to elicit effective CTL responses in humans. Such a vaccine could improve viral control in patients who later become infected, thereby reducing onwards transmission and enhancing life expectancy in the absence of treatment. The ability of HIV to evolve mutations that evade CTLs and the ability of these ‘escape mutants’ to spread amongst the population poses a challenge to the development of an effective and robust vaccine. We present a mathematical model of within-host evolution and between-host transmission of CTL escape mutants amongst a population receiving a vaccine that elicits CTL responses to multiple epitopes. Within-host evolution at each epitope is represented by the outgrowth of escape mutants in hosts who restrict the epitope and their reversion in hosts who do not restrict the epitope. We use this model to investigate how the evolution and spread of escape mutants could affect the impact of a vaccine. We show that in the absence of escape, such a vaccine could markedly reduce the prevalence of both infection and disease in the population. However the impact of such a vaccine could be significantly abated by CTL escape mutants, especially if their selection in hosts who restrict the epitope is rapid and their reversion in hosts who do not restrict the epitope is slow. We also use the model to address whether a vaccine should span a broad or narrow range of CTL epitopes and target epitopes restricted by rare or common HLA types. We discuss the implications and limitations of our findings., Author Summary The evolution and spread of HIV strains that evade the immune response poses a major challenge to the development of an effective and robust HIV vaccine. We present a new mathematical tool that we use to dissect the drivers of the spread of these ‘immune escape mutants’ in a vaccinated population. Our study focuses on a vaccine that can reduce infectiousness and enhance longevity but does not provide sterilizing immunity. We show that in the absence of escape such a vaccine could reduce the prevalence of both infection and disease in the population. However, vaccine impact could be significantly abated by immune escape mutants, especially if they emerge rapidly and revert very slowly after transmission to hosts in whom the original selection pressure is absent. We also discuss the effect that vaccine breadth and the frequency with which different epitopes are targeted have upon vaccine impact.

The combination of mathematical modelling and data analysis to understand the within-host dynamics of human immunodeficiency virus (HIV) infections has been one of the most informative uses of mathematical biology in the last decade. Simple models of viral dynamics together with viral load measurements provided an early estimate that the turnover of HIV infected cells is very rapid: most do not survive beyond 1 day. Although this estimate was initially a surprise to the field, further corroborating evidence has made it widely accepted. More recently, within-host models have been used to investigate the efficacy of cytotoxic T-lymphocytes (CTLs) in controlling HIV infection. Though there is clear experimental evidence that they play some role, the magnitude of this role remains contentious. Models have offered three insights on this topic. Firstly, in chronically infected humans fewer than 20% of HIV-infected cell death is attributed to killing by CTLs. Secondly, CTLs are more efficient in acute infection than chronic infection, but not dramatically so, and thirdly, CTLs are markedly more efficient in simian than human immunodeficiency viral infection. Although based on simple models and repeatable data, the main prediction of this work that CTL vaccines might work in macaques but not in humans is yet to gain recognition. This is despite the fact that this prediction was borne out by the failure of STEP vaccine. We contend that in time this assertion too will become more widely accepted.

To determine the relative fitness of oseltamivir-resistant strains compared to susceptible wild-type viruses, we combined mathematical modeling and statistical techniques with a novel in vivo “competitive-mixtures” experimental model. Ferrets were coinfected with either pure populations (100% susceptible wild-type or 100% oseltamivir-resistant mutant virus) or mixed populations of wild-type and oseltamivir-resistant influenza viruses (80%:20%, 50%:50%, and 20%:80%) at equivalent infectivity titers, and the changes in the relative proportions of those two viruses were monitored over the course of the infection during within-host and over host-to-host transmission events in a ferret contact model. Coinfection of ferrets with mixtures of an oseltamivir-resistant R292K mutant A(H3N2) virus and a R292 oseltamivir-susceptible wild-type virus demonstrated that the R292K mutant virus was rapidly outgrown by the R292 wild-type virus in artificially infected donor ferrets and did not transmit to any of the recipient ferrets. The competitive-mixtures model was also used to investigate the fitness of the seasonal A(H1N1) oseltamivir-resistant H274Y mutant and showed that within infected ferrets the H274Y mutant virus was marginally outgrown by the wild-type strain but demonstrated equivalent transmissibility between ferrets. This novel in vivo experimental method and accompanying mathematical analysis provide greater insight into the relative fitness, both within the host and between hosts, of two different influenza virus strains compared to more traditional methods that infect ferrets with only pure populations of viruses. Our statistical inferences are essential for the development of the next generation of mathematical models of the emergence and spread of oseltamivir-resistant influenza in human populations.

Strong competition between cytotoxic T-lymphocytes (CTLs) specific for different epitopes in human immunodeficiency virus (HIV) infection would have important implications for the design of an HIV vaccine. To investigate evidence for this type of competition, we analysed CTL response data from 97 patients with chronic HIV infection who were frequently sampled for up to 96 weeks. For each sample, CTL responses directed against a range of known epitopes in gag, pol and nef were measured using an enzyme-linked immunospot assay. The Lotka–Volterra model of competition was used to predict patterns that would be expected from these data if competitive interactions materially affect CTL numbers. In this application, the model predicts that when hosts make responses to a larger number of epitopes, they would have diminished responses to each epitope and that if one epitope-specific response becomes dramatically smaller, others would increase in size to compensate; conversely if one response grows, others would shrink. Analysis of the experimental data reveals results that are wholly inconsistent with these predictions. In hosts who respond to more epitopes, the average epitope-specific response tends to be larger, not smaller. Furthermore, responses to different epitopes almost always increase in unison or decrease in unison. Our findings are therefore inconsistent with the hypothesis that there is competition between CTL responses directed against different epitopes in HIV infection. This suggests that vaccines that elicit broad responses would be favourable because they would direct a larger total response against the virus, in addition to being more robust to the effects of CTL escape., Proceedings of the Royal Society B: Biological Sciences, 276 (1677), ISSN:0080-4649, ISSN:0950-1193, ISSN:1471-2954, ISSN:0962-8452

Background We aimed to characterize the molecular epidemiology of HIV type-1 (HIV-1) and the prevalence of drug- associated mutations prior to initiating highly active antiretroviral therapy (HAART) in the Free State province, South Africa. The Free State has a population of 3 million, an antenatal HIV prevalence of approximately 34% and a well established infrastucture for antiretroviral (ARV) provision. Methods HIV-1 polymerase genes were sequenced from 425 HAART-naive HIV-1-positive patients at voluntary primary healthcare HIV testing centres, who were subsequently attending district centres for assessment for commencing ARVs. Patients (>18 years) were sampled randomly with no exclusion for gender or clinical criteria. Sequences were analysed according to phylogeny and drug resistance. Results Phylogenetic clustering within the cohort was suggestive of multiple introductions of subtype C virus into the region. Drug resistance mutations (according to the International AIDS Society-USA classification) were distributed randomly across the cohort phylogeny with an overall prevalence of 2.3% in the sampled patients. When stratified according to CD4+ T-cell count, the prevalence of resistance was 3.6%, 0.9% and 1.2% for CD4+ T-cell counts 500 cells/μ l, respectively, and was most common for non-nucleoside reverse transcriptase inhibitor resistance (3.1% in patients with CD4+ T-cell count + T-cell counts ( P=0.003), suggesting unrecognized exposure to ARVs. Conclusions In the Free State population, there was a statistical association between low CD4+ T-cell counts and drug-associated viral polymorphisms. Our data advocate the benefit of detailed history taking from patients starting HAART at low CD4+ T-cell counts with close follow-up of the virological response.

Although no naturally infected sheep with bovine spongiform encephalopathy (BSE) has ever been discovered, it remains possible that BSE once infected the UK sheep population, has been transmitted between sheep, and is still present today. We constructed a mathematical model to assess the current maximum theoretical exposure to consumers from BSE-infected ovine material and to estimate the risk reduction that could be achieved by abattoir-based control options if BSE-infected sheep were ever found in the national flock. We predict that, if present, the exposure to consumers from a single BSE-infected sheep would be high: one sheep, close to the end of its incubation period, is likely to contribute 10–1000 times more infectious material than a fully infectious cow. Furthermore, 30% of this exposure comes from infectivity residing in lymphatic and peripheral tissue that cannot be completely removed from a carcass. We are 95% confident that throughout Great Britain, no more than four sheep flocks currently harbour an ongoing BSE epidemic. However, since the exposure from a single infected sheep is high, the annual human exposure from four ‘typical’ BSE-infected flocks could be considerable. Small reductions in exposure could be achieved by strategies based on tissue testing, a 12-month age restriction or expanded definitions of high-risk tissues. A six-month age restriction is likely to be more effective and genotype-based strategies the most effective.