Modelling HPV Vaccination and Screening Strategies to Optimize Treatment

HPV is a common sexually transmitted infection found worldwide which can lead to serious health effects. While HPV has a high regression rate, if it does progress, it can cause various cancers (i.e. cervical, penile, throat). It is possible to minimize the mal-effects of HPV with tools such as screening, vaccination and treatment. Three sets of compartmental models were developed to study various aspects of HPV infection and progression. The first set of models studies which parameters are relevant in screening and vaccination programs and compares four different programs: a no intervention program, a screening only intervention program, a vaccination only program, and a screening and vaccination program. The second set of models compares various screening programs, including a co-screening program. The purpose of this set of models is to complete a cost analysis on the models, as well as to compare them epidemiologically. The third set of models studies the phenomenon of infection and re-infection with HPV. This chapter includes both single HPV type models and multi-type HPV models. All three sets of models lead to the same conclusions that HPV screening is essential in the minimization of HPV and cervical cancer. Furthermore, both screening and vaccination are essential in lowering the basic reproduction number

Deterministic and Stochastic Modeling of Human Papillomavirus Gene Regulatory Network

In this thesis a novel stochastic and deterministic mathematical model of Human papillomavirus (HPV) gene regulatory network was developed. The novelty of this project is both on methodological and biological /clinical site. The former is in line with the current challenge in recent years to have a holistic view of the basics regulatory mechanisms interconnected to form a complex machinery, where complex patterns can arise, only form the interconnection of basics modules. In fact, HPV offers a case of study of great interest in molecular systems biology. It involves a number of relevant regulatory mechanisms (e.g. transcription, translation, promoter modulation, polyadenylation regulation, splicing,…) connected together to form a complex network, albeit its genome is relatively simple, thus suitable for an accurate deterministic and even stochastic modeling. HPVs cause a series of diseases of the cutaneous and mucosal epithelium, ranging from minor lesions to precancerous cervical lesions and cervical cancer, which is considered one of the most common cancer in the women worldwide. Therefore, on the biological/clinical aspect the development of a mathematical model of HPV gene expression, is of great interest in order to dispose of an in silico simulator useful to achieve a better comprehension of the complex gene regulatory network, and capable to predict different scenarios from the first stages of viral infection up to a cervical cancer condition. As far as we know, there is no model of HPV gene regulation available in literature. A new synthesis of the HPV molecular biology with especial regard to gather/infer from literature the parameters useful for designing a dynamical model, and to shed light in what is still lacking in the biological literature, was preformed. The biological knowledge was translated into a stochastic model in terms of biochemical reactions. In particular, we modeled the HPV early and late promoters that account for the transcripts and proteins evolution during the entire viral life cycle. Even the post-transcriptional and post-translational modifications were modeled in order to properly capture the complex viral regulation known from literature. As far as we know, it is the first time a stochastic model accounts for the complex post-transcriptional control, modeling the splicing and polyadenylation sites regulation, and connect this latter to the transcriptional control layer, mediated by the promoters activities, in order to explore complex patterns that can arise only from the interconnection of different control layers. The Master Equation (ME) of the system was considered in order to predict and investigate its stochastic behavior. Because of the complex system structure it wasn't possible to solve the whole ME analytically, hence numerical exact simulations were performed by means of the Gillespie's algorithm. A quasi-equilibrium approximation of the ME was developed in order to get a deterministic approximation of the model. The model structure together with the fixed parameters we have gathered/inferred from literature was able to fit a dataset consistent of the early promoter activity and to qualitatively reproduce the main dynamical behavior of two of the most important regulatory transcripts during viral late phase. Different in silico experiments were designed to opportunely explore both the capability of the stochastic model to follows the deterministic predictions, when in fast fluctuations regimen, and to discover complex stochastic patterns, that can arise through the interconnection of the transcriptional and post-transcriptional control layers. In general, both the stochastic and deterministic formulation of the model showed the capability to reproduce the HPV gene expression dynamics, during the entire viral life cycle, in good agreement with the current biological knowledge

A mathematical investigation of the effects of sexual orientation and HIV status on HPV transmission and vaccination

The effect of the inclusion of sexual behaviour, particularly three sexual orientation classes, on the transmission dynamics of HPV and cervical cancer incidence was investigated. A comprehensive literature review of mathematical models of HPV transmission and the natural history of cervical cancer was concluded. A mathematical model using ordinary differential equations was developed, which incorporated the three sexual orientation classes, and a sexual mixing algorithm for modelling the transmission dynamics. Reproduction numbers, determined through a simplified version of the developed model, indicated that the bisexual population could form a bridge between the heterosexual and homosexual population. The level of interaction is determined by the selection preferences of a bisexual individual to form a partnership with an individual of the same or opposite sex. The model was simulated, with parameters based on a South African population and HPV type 16/18, to investigate the effects of HIV status, sexual orientation and various vaccination strategies on HPV transmission and cervical cancer incidence. The results indicated that HIV status is a significant factor when determining cervical cancer incidence. The results regarding vaccination strategies agreed with results from the literature review with a two sex before sexual debut and catch up program the most effective, noting that with increased vaccination coverage of females the marginal impact on cervical cancer incidence of this approach diminished

Trends in Infectious Diseases

This book gives a comprehensive overview of recent trends in infectious diseases, as well as general concepts of infections, immunopathology, diagnosis, treatment, epidemiology and etiology to current clinical recommendations in management of infectious diseases, highlighting the ongoing issues, recent advances, with future directions in diagnostic approaches and therapeutic strategies. The book focuses on various aspects and properties of infectious diseases whose deep understanding is very important for safeguarding human race from more loss of resources and economies due to pathogens

Analysis of Human Papillomavirus Capsid Proteins: Insights into Capsid Assembly

Abstract: Papillomaviruses (PVs) are double stranded (ds)-DNA viruses (~8-kbp), which infect mucosal and cutaneous epithelial cells from various mammalian species, causing tumors in both epithelial cell-types. During the late-phase, the capsid proteins (L1 and L2), are expressed to encapsidate the viral genome generating infectious virion particles required for PV. Natural PV infections produce morphologically homogenous progeny virions 55-nm in diameter. Transient transfection systems allow individual expression of the capsid proteins, which are able to produce low-levels of infectious virion-like particles (VLPs) and non-infectious VLPs that have the capacity to resemble and function as wild-type virions. Results: The research herein demonstrates the conserved sequence homology amongst the variety of PV L2 proteins reveals its necessity and conserved role during PV infections. The L1 and L2 DNA-binding domains were bioinformatically analyzed and the results showed amino acid sequence homology amongst all PV genera. The L2 DNA-BDs have sequence homology in comparison to the DNA-binding proteins from three species within the Microviridae family (ex. φX174, alpha-3). Previously, reports demonstrate the L2 protein interacting with the PV encoded E2, trans-regulatory, protein. The studies herein discover a novel interaction between the E2 and L1 protein of HPV16. The L1-to-E2 interaction is highly dynamic and may be dependent upon the spontaneous oligomerization of the L1 protein. Use of the Cluspro docking software predicts E2 to interact with the BC-loop (49-61 a.a.) and HI-loop (341-362 a.a) of the L1 protein, localized within the valley/cleft of the known pentamer-to-pentamer interactions. Advisor: Peter Angelett

Analysis of Human Papillomavirus Capsid Proteins: Insights into Capsid Assembly

Abstract: Papillomaviruses (PVs) are double stranded (ds)-DNA viruses (~8-kbp), which infect mucosal and cutaneous epithelial cells from various mammalian species, causing tumors in both epithelial cell-types. During the late-phase, the capsid proteins (L1 and L2), are expressed to encapsidate the viral genome generating infectious virion particles required for PV. Natural PV infections produce morphologically homogenous progeny virions 55-nm in diameter. Transient transfection systems allow individual expression of the capsid proteins, which are able to produce low-levels of infectious virion-like particles (VLPs) and non-infectious VLPs that have the capacity to resemble and function as wild-type virions. Results: The research herein demonstrates the conserved sequence homology amongst the variety of PV L2 proteins reveals its necessity and conserved role during PV infections. The L1 and L2 DNA-binding domains were bioinformatically analyzed and the results showed amino acid sequence homology amongst all PV genera. The L2 DNA-BDs have sequence homology in comparison to the DNA-binding proteins from three species within the Microviridae family (ex. φX174, alpha-3). Previously, reports demonstrate the L2 protein interacting with the PV encoded E2, trans-regulatory, protein. The studies herein discover a novel interaction between the E2 and L1 protein of HPV16. The L1-to-E2 interaction is highly dynamic and may be dependent upon the spontaneous oligomerization of the L1 protein. Use of the Cluspro docking software predicts E2 to interact with the BC-loop (49-61 a.a.) and HI-loop (341-362 a.a) of the L1 protein, localized within the valley/cleft of the known pentamer-to-pentamer interactions. Advisor: Peter Angelett

Sensitivity analysis methods for dynamical models

Sensitivity analysis methods are widely applied to study biological systems in order to investigate the effect of parameter change on the solutions of mathematical models. In this work, conventional Parametric Sensitivity Analysis main methods were reviewed along with the novel analysis called Impulse Parametric Sensitivity Analysis presented by Perumal et al. Both analysis were then applied on the HPV early promoter regulation model presented by Giaretta et al. and their results were compare

Advancing Epidemiological Science Through Computational Modeling: A Review with Novel Examples

Computational models have been successfully applied to a wide variety of research areas including infectious disease epidemiology. Especially for questions that are difficult to examine in other ways, computational models have been used to extend the range of epidemiological issues that can be addressed, advance theoretical understanding of disease processes and help identify specific intervention strategies. We explore each of these contributions to epidemiology research through discussion and examples. We also describe in detail models for raccoon rabies and methicillin-resis-tant Staphylococcus aureus, drawn from our own research, to further illustrate the role of computation in epidemiological modeling

Human Papillomavirus and Related Diseases

Cervical cancer is the second most prevalent cancer among women worldwide, and infection with Human Papilloma Virus (HPV) has been identified as the causal agent for this condition. The natural history of cervical cancer is characterized by slow disease progression, rendering the condition in essence preventable and even treatable when diagnosed in early stages. Pap smear and the recently introduced prophylactic vaccines are the most prominent prevention options, but despite the availability of these primary and secondary screening tools, the global burden of disease is unfortunately still very high This book will focus on the clinical and diagnostic aspects of HPV and related disease, highlighting the latest developments in this field

2015 Conference Abstracts: Annual Undergraduate Research Conference at the Interface of Biology and Mathematics

Schedule and abstract book for the Seventh Annual Undergraduate Research Conference at the Interface of Biology and Mathematics Date: November 21-22, 2015Plenary speaker: Robert Smith, University of OttawaFeatured speaker: Rachel Lenhart, University of Wisconsin, Madiso