Laura W. Pomeroy

Cardiovascular risk evaluation and antiretroviral therapy effects in an HIV cohort: implications for clinical management: the CREATE 1 study

Aims:  The aim of this study is to determine the cardiovascular disease (CVD) risk profile of a large UK HIV cohort and how highly active antiretroviral therapy (HAART) affects this.

Molecular Analysis of H7 Avian Influenza Viruses from Australia and New Zealand: Genetic Diversity and Relationships from 1976 to 2007

ABSTRACT Full-genome sequencing of 11 Australian and 1 New Zealand avian influenza A virus isolate (all subtype H7) has enabled comparison of the sequences of each of the genome segments to those of other subtype H7 avian influenza A viruses. The inference of phylogenetic relationships for each segment has been used to develop a model of the natural history of these viruses in Australia. Phylogenetic analysis of the hemagglutinin segment indicates that the Australian H7 isolates form a monophyletic clade. This pattern is consistent with the long-term, independent evolution that is, in this instance, associated with geographic regions. On the basis of the analysis of the other H7 hemagglutinin sequences, three other geographic regions for which similar monophyletic clades have been observed were confirmed. These regions are Eurasia plus Africa, North America, and South America. Analysis of the neuraminidase sequences from the H7N1, H7N3, and H7N7 genomes revealed the same region-based relationships. This pattern of independent evolution of Australian isolates is supported by the results of analysis of each of the six remaining genomic segments. These results, in conjunction with the occurrence of five different combinations of neuraminidase subtypes (H7N2, H7N3, H7N4, H7N6, H7N7) among the 11 Australian isolates, suggest that the maintenance host(s) is nearly exclusively associated with Australia. The single lineage of Australian H7 hemagglutinin sequences, despite the occurrence of multiple neuraminidase types, suggests the existence of a genetic pool from which a variety of reassortants arise rather than the presence of a small number of stable viral clones. This pattern of evolution is likely to occur in each of the regions mentioned above.

Increased Sensitivity of CD4+ T-Effector Cells to CD4+CD25+ Treg Suppression Compensates for Reduced Treg Number in Asymptomatic HIV-1 Infection

Background In HIV infection, uncontrolled immune activation and disease progression is attributed to declining CD4+CD25+FoxP3+ regulatory T-cell (Treg) numbers. However, qualitative aspects of Treg function in HIV infection, specifically the balance between Treg cell suppressive potency versus suppressibility of effector cells, remain poorly understood. This report addresses this issue. Methodology/Principal Findings A classic suppression assay to measure CD4+CD45RO+CD25hi Treg cells to suppress the proliferation of CD4+CD45RO+CD25− effectors cells (E) following CD3/CD28 polyclonal stimulation was employed to compare the suppressive ability of healthy volunteers (N = 27) and chronic, asymptomatic, treatment naïve, HIV-infected subjects (N = 14). HIV-infected subjects displayed significantly elevated Treg-mediated suppression compared to healthy volunteers (p = 0.0047). Cross-over studies comparing Treg cell potency from HIV-infected versus control subjects to suppress the proliferation of a given population of allogeneic effector cells demonstrated increased sensitivity of CD4+CD25− effector cells from HIV-infected subjects to be suppressed, associated with reduced production of the Treg counter-regulatory cytokine, IL-17, rather than an increase in the suppressive potential of their CD4+CD25+ Treg cells. However, compared to controls, HIV+ subjects had significantly fewer absolute numbers of circulating CD4+CD25+FoxP3+ Treg cells. In vitro studies highlighted that one mechanism for this loss could be the preferential infection of Treg cells by HIV. Conclusions/Significance Together, novel data is provided to support the contention that elevated Treg-mediated suppression may be a natural host response to HIV infection

Serotype Diversity of Foot‐and‐Mouth‐Disease Virus in Livestock without History of Vaccination in the Far North Region of Cameroon

Little information is available about the natural cycle of foot-and-mouth disease (FMD) in the absence of control measures such as vaccination. Cameroon presents a unique opportunity for epidemiological studies because FMD vaccination is not practiced. We carried out a prospective study including serological, antigenic and genetic aspects of FMD virus (FMDV) infections among different livestock production systems in the Far North of Cameroon to gain insight into the natural ecology of the virus. We found serological evidence of FMDV infection in over 75% of the animals sampled with no significant differences of prevalence observed among the sampled groups (i.e. market, sedentary, transboundary trade and mobile). We also found antibodies reactive to five of the seven FMDV serotypes (A, O, SAT1, SAT2 and SAT3) among the animals sampled. Finally, we were able to genetically characterize viruses obtained from clinical and subclinical FMD infections in Cameroon. Serotype O viruses grouped into two topotypes (West and East Africa). SAT2 viruses grouped with viruses from Central and Northern Africa, notably within the sublineage causing the large epidemic in Northern Africa in 2012, suggesting a common origin for these viruses. This research will guide future interventions for the control of FMD such as improved diagnostics, guidance for vaccine formulation and epidemiological understanding in support of the progressive control of FMD in Cameroon.

Reassortment Networks and the Evolution of Pandemic H1N1 Swine-Origin Influenza

Prior research developed Reassortment Networks to reconstruct the evolution of segmented viruses under both reassortment and mutation. We report their application to the swine-origin pandemic H1N1 virus (S-OIV). A database of all influenza A viruses, for which complete genome sequences were available in Genbank by October 2009, was created and dynamic programming was used to compute distances between all corresponding segments. A reassortment network was created to obtain the minimum cost evolutionary paths from all viruses to the exemplar S-OIV A/California/04/2009. This analysis took 35 hours on the Cray Extreme Multithreading (XMT) supercomputer, which has special hardware to permit efficient parallelization. Six specific H1N1/H1N2 bottleneck viruses were identified that almost always lie on minimum cost paths to S-OIV. We conjecture that these viruses are crucial to S-OIV evolution and worthy of careful study from a molecular biology viewpoint. In phylogenetics, ancestors are typically medians that have no functional constraints. In our method, ancestors are not inferred, but rather chosen from previously observed viruses along a path of mutation and reassortment leading to the target virus. This specificity and functional constraint render our results actionable for further experiments in vitro and in vivo.

Spatial and Temporal Characteristics of Pastoral Mobility in the Far North Region, Cameroon: Data Analysis and Modeling

Modeling the movements of humans and animals is critical to understanding the transmission of infectious diseases in complex social and ecological systems. In this paper, we focus on the movements of pastoralists in the Far North Region of Cameroon, who follow an annual transhumance by moving between rainy and dry season pastures. Describing, summarizing, and modeling the transhumance movements in the region are important steps for understanding the role these movements may play in the transmission of infectious diseases affecting humans and animals. We collected data on this transhumance system for four years using a combination of surveys and GPS mapping. An analysis on the spatial and temporal characteristics of pastoral mobility suggests four transhumance modes, each with its own properties. Modes M1 and M2 represent the type of transhumance movements where pastoralists settle in a campsite for a relatively long period of time (≥20 days) and then move around the area without specific directions within a seasonal grazing area. Modes M3 and M4 on the other hand are the situations when pastoralists stay in a campsite for a relatively short period of time (<20 days) when moving between seasonal grazing areas. These four modes are used to develop a spatial-temporal mobility (STM) model that can be used to estimate the probability of a mobile pastoralist residing at a location at any time. We compare the STM model with two reference models and the experiments suggest that the STM model can effectively capture and predict the space-time dynamics of pastoral mobility in our study area.

Serotype-Specific Transmission and Waning Immunity of Endemic Foot-and-Mouth Disease Virus in Cameroon

Foot-and-mouth disease virus (FMDV) causes morbidity and mortality in a range of animals and threatens local economies by acting as a barrier to international trade. The outbreak in the United Kingdom in 2001 that cost billions to control highlighted the risk that the pathogen poses to agriculture. In response, several mathematical models have been developed to parameterize and predict both transmission dynamics and optimal disease control. However, a lack of understanding of the multi-strain etiology prevents characterization of multi-strain dynamics. Here, we use data from FMDV serology in an endemic setting to probe strain-specific transmission and immunodynamics. Five serotypes of FMDV affect cattle in the Far North Region of Cameroon. We fit both catalytic and reverse catalytic models to serological data to estimate the force of infection and the rate of waning immunity, and to detect periods of sustained transmission. For serotypes SAT2, SAT3, and type A, a model assuming life-long immunity fit better. For serotypes SAT1 and type O, the better-fit model suggests that immunity may wane over time. Our analysis further indicates that type O has the greatest force of infection and the longest duration of immunity. Estimates for the force of infection were time-varying and indicated that serotypes SAT1 and O displayed endemic dynamics, serotype A displayed epidemic dynamics, and SAT2 and SAT3 did not sustain local chains of transmission. Since these results were obtained from the same population at the same time, they highlight important differences in transmission specific to each serotype. They also show that immunity wanes at rates specific to each serotype, which influences patterns of local persistence. Overall, this work shows that viral serotypes can differ significantly in their epidemiological and immunological characteristics. Patterns and processes that drive transmission in endemic settings must consider complex viral dynamics for accurate representation and interpretation.

Data‐Driven Models of Foot‐and‐Mouth Disease Dynamics: A Review

Foot-and-mouth disease virus (FMDV) threatens animal health and leads to considerable economic losses worldwide. Progress towards minimizing both veterinary and financial impact of the disease will be made with targeted disease control policies. To move towards targeted control, specific targets and detailed control strategies must be defined. One approach for identifying targets is to use mathematical and simulation models quantified with accurate and fine-scale data to design and evaluate alternative control policies. Nevertheless, published models of FMDV vary in modelling techniques and resolution of data incorporated. In order to determine which models and data sources contain enough detail to represent realistic control policy alternatives, we performed a systematic literature review of all FMDV dynamical models that use host data, disease data or both data types. For the purpose of evaluating modelling methodology, we classified models by control strategy represented, resolution of models and data, and location modelled. We found that modelling methodology has been well developed to the point where multiple methods are available to represent detailed and contact-specific transmission and targeted control. However, detailed host and disease data needed to quantify these models are only available from a few outbreaks. To address existing challenges in data collection, novel data sources should be considered and integrated into models of FMDV transmission and control. We suggest modelling multiple endemic areas to advance local control and global control and better understand FMDV transmission dynamics. With incorporation of additional data, models can assist with both the design of targeted control and identification of transmission drivers across geographic boundaries.

Elevated effector cell sensitivity to Treg-cell suppression that is not associated with reduced Th17-cell expression distinguishes HIV+ asymptomatic subjects from progressors

Suppression mediated by Treg cells is a balance between Treg‐cell suppressive potency versus sensitivity of effector cells to Treg‐cell suppression. We assessed if this balance, along with Treg‐cell number relative to the Treg‐cell counter‐regulatory cytokine IL‐17, differs between asymptomatic HIV+ subjects versus those who progress onto disease. Cross‐over studies comparing Treg‐cell potency, measured by effector cell proliferation or IFN‐γ expression, from HIV‐infected versus control subjects to suppress the proliferation of allogeneic control effector cells demonstrated increased sensitivity of CD4+CD25− effector cells from asymptomatic HIV+ subjects to suppression, rather than an increase in the suppressive potential of their CD4+CD25+ Treg cells. In contrast, HIV+ progressors did not differ from controls in Treg‐cell potency or effector cell sensitivity to Treg‐cell suppression. Both CD4+CD25+Foxp3+ Treg and effector IL‐17 absolute cell numbers were significantly lower in all HIV+ subjects tested and not restored by antiviral therapy. Thus, these novel data suggest that elevated Treg‐cell‐mediated suppression due to increased sensitivity of effectors to Treg cells may be a natural host response in chronic asymptomatic HIV infection, which is lost as disease progresses and that this feature of CD25− effector cells is not inextricably linked to reduced production of the Treg‐cell counter‐regulatory cytokine IL‐17.

Multi-species SIR models from a dynamical Bayesian perspective

Multi-species compartment epidemic models, such as the multi-species susceptible–infectious–recovered (SIR) model, are extensions of the classic SIR models, which are used to explore the transient dynamics of pathogens that infect multiple hosts in a large population. In this article, we propose a dynamical Bayesian hierarchical SIR (HSIR) model, to capture the stochastic or random nature of an epidemic process in a multi-species SIR (with recovered becoming susceptible again) dynamical setting, under hidden mass balance constraints. We call this a Bayesian hierarchical multi-species SIR (MSIRB) model. Different from a classic multi-species SIR model (which we call MSIRC), our approach imposes mass balance on the underlying true counts rather than, improperly, on the noisy observations. Moreover, the MSIRB model can capture the discrete nature of, as well as uncertainties in, the epidemic process.