Gareth Hughes

Episodic Sexual Transmission of HIV Revealed by Molecular Phylodynamics

Background The structure of sexual contact networks plays a key role in the epidemiology of sexually transmitted infections, and their reconstruction from interview data has provided valuable insights into the spread of infection. For HIV, the long period of infectivity has made the interpretation of contact networks more difficult, and major discrepancies have been observed between the contact network and the transmission network revealed by viral phylogenetics. The high rate of HIV evolution in principle allows for detailed reconstruction of links between virus from different individuals, but often sampling has been too sparse to describe the structure of the transmission network. The aim of this study was to analyze a high-density sample of an HIV-infected population using recently developed techniques in phylogenetics to infer the short-term dynamics of the epidemic among men who have sex with men (MSM). Methods and Findings Sequences of the protease and reverse transcriptase coding regions from 2,126 patients, predominantly MSM, from London were compared: 402 of these showed a close match to at least one other subtype B sequence. Nine large clusters were identified on the basis of genetic distance; all were confirmed by Bayesian Monte Carlo Markov chain (MCMC) phylogenetic analysis. Overall, 25% of individuals with a close match with one sequence are linked to 10 or more others. Dated phylogenies of the clusters using a relaxed clock indicated that 65% of the transmissions within clusters took place between 1995 and 2000, and 25% occurred within 6 mo after infection. The likelihood that not all members of the clusters have been identified renders the latter observation conservative. Conclusions Reconstruction of the HIV transmission network using a dated phylogeny approach has revealed the HIV epidemic among MSM in London to have been episodic, with evidence of multiple clusters of transmissions dating to the late 1990s, a period when HIV prevalence is known to have doubled in this population. The quantitative description of the transmission dynamics among MSM will be important for parameterization of epidemiological models and in designing intervention strategies.

Transmission network parameters estimated from HIV sequences for a nationwide epidemic.

Background. Many studies of sexual behavior have shown that individuals vary greatly in their number of sexual partners over time, but it has proved difficult to obtain parameter estimates relating to the dynamics of human immunodeficiency virus (HIV) transmission except in small-scale contact tracing studies. Recent developments in molecular phylodynamics have provided new routes to obtain these parameter estimates, and current clinical practice provides suitable data for entire infected populations. Methods. A phylodynamic analysis was performed on partial pol gene sequences obtained for routine clinical care from 14 560 individuals, representing approximately 60% of the HIV-positive men who have sex with men (MSM) under care in the United Kingdom. Results. Among individuals linked to others in the data set, 29% are linked to only 1 individual, 41% are linked to 2–10 individuals, and 29% are linked to ≥10 individuals. The right-skewed degree distribution can be approximated by a power law, but the data are best fitted by a Waring distribution for all time depths. For time depths of 5–7 years, the distribution parameter ρ lies within the range that indicates infinite variance. Conclusions. The transmission network among UK MSM is characterized by preferential association such that a randomly distributed intervention would not be expected to stop the epidemic.

Molecular Phylodynamics of the Heterosexual HIV Epidemic in the United Kingdom

The heterosexual risk group has become the largest HIV infected group in the United Kingdom during the last 10 years, but little is known of the network structure and dynamics of viral transmission in this group. The overwhelming majority of UK heterosexual infections are of non-B HIV subtypes, indicating viruses originating among immigrants from sub-Saharan Africa. The high rate of HIV evolution, combined with the availability of a very high density sample of viral sequences from routine clinical care has allowed the phylodynamics of the epidemic to be investigated for the first time. Sequences of the viral protease and partial reverse transcriptase coding regions from 11,071 patients infected with HIV of non-B subtypes were studied. Of these, 2774 were closely linked to at least one other sequence by nucleotide distance. Including the closest sequences from the global HIV database identified 296 individuals that were in UK-based groups of 3 or more individuals. There were a total of 8 UK-based clusters of 10 or more, comprising 143/2774 (5%) individuals, much lower than the figure of 25% obtained earlier for men who have sex with men (MSM). Sample dates were incorporated into relaxed clock phylogenetic analyses to estimate the dates of internal nodes. From the resulting time-resolved phylogenies, the internode lengths, used as estimates of maximum transmission intervals, had a median of 27 months overall, over twice as long as obtained for MSM (14 months), with only 2% of transmissions occurring in the first 6 months after infection. This phylodynamic analysis of non-B subtype HIV sequences representing over 40% of the estimated UK HIV-infected heterosexual population has revealed heterosexual HIV transmission in the UK is clustered, but on average in smaller groups and is transmitted with slower dynamics than among MSM. More effective intervention to restrict the epidemic may therefore be feasible, given effective diagnosis programmes.

MOLECULAR EPIDEMIOLOGY OF TERRESTRIAL RABIES IN THE FORMER SOVIET UNION

Fifty-five rabies virus isolates originating from different regions of the former Soviet Union (FSU) were compared with isolates originating from Eurasia, Africa, and North America according to complete or partial nucleoprotein (N) gene sequences. The FSU isolates formed five distinct groups. Group A represented viruses originating from the Arctic, which were similar to viruses from Alaska and Canada. Group B consisted of “Arctic-like” viruses, originating from the south of East Siberia and the Far East. Group C consisted of viruses circulating in the steppe and forest-steppe territories from the European part of Russia to Tuva and in Kazakhstan. These three phylogenetic groups were clearly different from the European cluster. Viruses of group D circulate near the western border of Russia. Their phylogenetic position is intermediate between group C and the European cluster. Group E consisted of viruses originating from the northwestern part of Russia and comprised a “northeastern Europe” group described earlier from the Baltic region. According to surveillance data, a specific host can be defined clearly only for group A (arctic fox; Alopex lagopus) and for the Far Eastern part of the group B distribution area (raccoon dog; Nyctereutes procyonoides). For other territories and rabies virus variants, the red fox (Vulpes vulpes) is the main virus reservoir. However, the steppe fox (Vulpes corsac), wolf (Canis lupus), and raccoon dog are also involved in virus circulation, depending on host population density. These molecular data, joined with surveillance information, demonstrate that the current fox rabies epizootic in the territory of the FSU developed independently of central and western Europe. No evidence of positive selection was found in the N genes of the isolates. In the glycoprotein gene, evidence of positive selection was strongly suggested in codons 156, 160, and 183. At these sites, no link between amino acid substitutions and phylogenetic placement or specific host species was detected.

Epidemiology: Foot-and-mouth disease under control in the UK

Following the first reported case on 20 February this year, foot-and-mouth disease spread to over 1,500 livestock farms in the United Kingdom by the end of April. From late March, the Ministry of Agriculture, Fisheries and Food (MAFF) required livestock on infected farms to be culled within 24 hours of the disease being reported and those on neighbouring farms within 48 hours. Here we investigate whether progress towards meeting these targets has had a detectable impact on the course of the epidemic in the United Kingdom. We conclude that it has now been brought under control, but it will be important to contain rapidly any new outbreaks in previously unaffected areas.

Incorporating spatial pattern of harmful organisms into crop loss models

Abstract Weeds, pests and pathogens (collectively, harmful organisms) tend to have patchy spatial patterns at the field scale. The idea that this patchiness may influence the way that harmful organisms compete with, or exploit, crop plants is not new. Recently, however, increasing economic and environmental pressures have led to a requirement for more accurate use of crop protection measures. This, in turn, requires more accurate predictions of populations of harmful organisms. Against this background, there have been attempts to develop a framework for the quantification of the effect of spatial pattern of harmful organisms on crop yield. There are two main elements of this framework: models of compensatory growth by healthy plants neighbouring affected ones; and models of intra-specific competition within the harmful organism population. Methods allowing the incorporation of these elements into models of crop loss to harmful organisms are reviewed. Thus far, practical implementation of crop loss models incorporating spatial pattern of harmful organisms has not been widespread. Further emphasis on field studies is likely to be necessary before this situation changes.

Plant disease incidence: inverse sampling, sequential sampling, and confidence intervals when observed mean incidence is zero

Abstract Sequential and inverse sampling equations were developed for estimating the mean proportion of diseased plants (or plant units), disease incidence (p), where the data were obtained by cluster sampling. With cluster sampling, the disease status of all n plants in each of N sampling units is determined. Derived sampling equations were applicable for up to three ways of specifying reliability or precision of estimated p, and the following conditions of spatial heterogeneity: i) random pattern, with data described by the binomial distribution; ii) aggregated pattern, with data described by the beta-binomial distribution, and constant degree of aggregation (assessed with the ρ index of the beta-binomial); and iii) aggregated pattern, with data described by the binary form of the power law, in which the observed (empirical) variance of incidence is a power function of the theoretical variance for a binomial distribution. For the third situation, aggregation can vary with p, such that ρ is a function of the power law parameters. A selection of the sequential estimation equations were evaluated by the simulated sampling from: 1) data sets of the incidence of grape vines infected by Eutypa lata, and 2) simulated data with beta-binomial distributions. Results on achieved (observed) coefficient of variation of estimated p(C), difference between observed and true p, and average sample number, were similar to that found for the analogous equations developed for noncluster simple random sampling of count data with no upper bound (e.g. insect counts). Equations also were developed to calculate confidence intervals for p as a function of n, N, and ρ, when all sampled observations are disease free. These equations used the approximation of the negative binomial to the beta-binomial distribution that applies when p is small.

Serial passage of foot-and-mouth disease virus in sheep reveals declining levels of viraemia over time

If an infectious agent is to maintain itself within a closed population by means of an unbroken serial chain of infections, it must maintain the level of infectiousness of individuals through time, or termination of the transmission chain is inevitable. One possible cause of diminution in infectiousness along serial chains of transmission may be that individuals are unable to amplify and transmit comparable levels of the infectious agent. Here, the results are reported of a novel experiment designed specifically to assess the effects of serial passage of foot-and-mouth disease virus (FMDV) in experimental groups of sheep. A virus isolate taken from an epidemic of foot-and-mouth disease (FMD) characterized by rapid fade-out of infection was passed serially through four groups of sheep housed in an isolation unit. Although it was not possible to measure individual infectiousness directly, blood virus load from infected individuals was quantified using a real-time PCR assay and used as an underlying indicator of the level of infection. The results of this assay concurred well with those of the traditional tissue-culture assay and were shown to be highly repeatable. The level of peak viraemia was shown to fall significantly with the time of infection and with passage group, both in terms of the group mean and regression analysis of individual values, suggesting that this isolate of FMDV may, under certain conditions, be unable to maintain itself indefinitely in susceptible sheep populations. The results of these experiments are discussed in terms of the epidemiology of FMD in sheep.

Porcine reproductive and respiratory syndrome virus: genetic diversity of recent British isolates.

Porcine reproductive and respiratory syndrome (PRRS) continues to be a significant problem for European pig producers, contributing to porcine respiratory disease complex, neonatal piglet mortality, infertility and occasional abortion storms. PRRS virus (PRRSV), a member of the arterivirus family with two defined major genotypes, has been shown to be quite genetically diverse. In the present study, genetic analysis of multiple gene regions of over 100 viruses isolated in Britain between 2003 and 2007 revealed that the diversity of British strains is now far greater than during the early 1990s. All isolates belong to genotype 1 (European). While some recent isolates are still very similar to early isolates, a wide range of more diverse viruses is now also circulating. Interestingly, some isolates were found to be very similar to a modified-live vaccine strain, and it is suggested that use of the vaccine has affected the evolution pattern of PRRS virus strains in Britain. Evidence of deletions in one viral gene, ORF3, and of genome recombination was also seen. A molecular clock model using the ORF7 sequences estimates the rate of substitution as 3.8 × 10(-3) per site per year, thereby dating the most recent common ancestor of all British viruses to 1991, coincident with the first outbreak of disease. Our findings therefore have implications for both the diagnostic and prophylactic methods currently being used, which are discussed.

Some methods for eliciting expert knowledge of plant disease epidemics and their application in cluster sampling for disease incidence

Abstract All formulae for the calculation of sample size require from the user some advance information relating to the population to be sampled. In the case of cluster sampling for disease incidence, sample size formulae based on the beta-binomial distribution require advance estimates of two parameters, describing the mean incidence and the level of aggregation. When this information is not available from previous experiments or surveys, expert knowledge of the pathosystem in question may provide a basis for its provision. Various methods for the elicitation of the required parameters from subjective assessments are described. The methods are based either on the beta probability density function for the probability of a plant being diseased or on the beta-binomial distribution for the number of diseased plants per sampling unit. Data from two previously published studies of plant virus disease incidence are used to illustrate some important features of these methods. Elicitation is likely to be more difficult when disease incidence is strongly aggregated than when aggregation is weak.