Multi-agent model of hepatitis C virus infection

Objectives: The objective of this study is to design a method for modeling hepatitis C virus (HCV) infection using multi-agent simulation and to verify it in practice. Methods and materials: In this paper, first, the modeling of HCV infection using a multi-agent system is compared with the most commonly used model type, which is based on differential equations. Then, the implementation and results of the model using a multi-agent simulation is presented. To find the values of the parameters used in the model, a method using inverted simulation flow and genetic algorithm is proposed. All of the data regarding HCV infection are taken from the paper describing the model based on the differential equation to which the proposed method is compared. Results: Important advantages of the proposed method are noted and demonstrated; these include flexibility, clarity, re-usability and the possibility to model more complex dependencies. Then, the simulation framework that uses the proposed approach is successfully implemented in C++ and is verified by comparing it to the approach based on differential equations. The verification proves that an objective function that performs the best is the function that minimizes the maximal differences in the data. Finally, an analysis of one of the already known models is performed, and it is proved that it incorrectly models a decay in the hepatocytes number by 40%. Conclusions: The proposed method has many advantages in comparison to the currently used model types and can be used successfully for analyzing HCV infection. With almost no modifications, it can also be used for other types of viral infections

Macaque models of human infectious disease.

Macaques have served as models for more than 70 human infectious diseases of diverse etiologies, including a multitude of agents-bacteria, viruses, fungi, parasites, prions. The remarkable diversity of human infectious diseases that have been modeled in the macaque includes global, childhood, and tropical diseases as well as newly emergent, sexually transmitted, oncogenic, degenerative neurologic, potential bioterrorism, and miscellaneous other diseases. Historically, macaques played a major role in establishing the etiology of yellow fever, polio, and prion diseases. With rare exceptions (Chagas disease, bartonellosis), all of the infectious diseases in this review are of Old World origin. Perhaps most surprising is the large number of tropical (16), newly emergent (7), and bioterrorism diseases (9) that have been modeled in macaques. Many of these human diseases (e.g., AIDS, hepatitis E, bartonellosis) are a consequence of zoonotic infection. However, infectious agents of certain diseases, including measles and tuberculosis, can sometimes go both ways, and thus several human pathogens are threats to nonhuman primates including macaques. Through experimental studies in macaques, researchers have gained insight into pathogenic mechanisms and novel treatment and vaccine approaches for many human infectious diseases, most notably acquired immunodeficiency syndrome (AIDS), which is caused by infection with human immunodeficiency virus (HIV). Other infectious agents for which macaques have been a uniquely valuable resource for biomedical research, and particularly vaccinology, include influenza virus, paramyxoviruses, flaviviruses, arenaviruses, hepatitis E virus, papillomavirus, smallpox virus, Mycobacteria, Bacillus anthracis, Helicobacter pylori, Yersinia pestis, and Plasmodium species. This review summarizes the extensive past and present research on macaque models of human infectious disease

Combination interventions for Hepatitis C and Cirrhosis reduction among people who inject drugs: An agent-based, networked population simulation experiment

Hepatitis C virus (HCV) infection is endemic in people who inject drugs (PWID), with prevalence estimates above 60 percent for PWID in the United States. Previous modeling studies suggest that direct acting antiviral (DAA) treatment can lower overall prevalence in this population, but treatment is often delayed until the onset of advanced liver disease (fibrosis stage 3 or later) due to cost. Lower cost interventions featuring syringe access (SA) and medically assisted treatment (MAT) for addiction are known to be less costly, but have shown mixed results in lowering HCV rates below current levels. Little is known about the potential synergistic effects of combining DAA and MAT treatment, and large-scale tests of combined interventions are rare. While simulation experiments can reveal likely long-term effects, most prior simulations have been performed on closed populations of model agents--a scenario quite different from the open, mobile populations known to most health agencies. This paper uses data from the Centers for Disease Control's National HIV Behavioral Surveillance project, IDU round 3, collected in New York City in 2012 by the New York City Department of Health and Mental Hygiene to parameterize simulations of open populations. Our results show that, in an open population, SA/MAT by itself has only small effects on HCV prevalence, while DAA treatment by itself can significantly lower both HCV and HCV-related advanced liver disease prevalence. More importantly, the simulation experiments suggest that cost effective synergistic combinations of the two strategies can dramatically reduce HCV incidence. We conclude that adopting SA/MAT implementations alongside DAA interventions can play a critical role in reducing the long-term consequences of ongoing infection

Infectious aetiology of marginal zone lymphoma and role of anti-infective therapy

Marginal zone lymphomas have been associated with several infectious agents covering both viral and bacterial pathogens and in some cases a clear aetiological role has been established. Pathogenetic mechanisms are currently not completely understood. However, the role of chronic stimulation of the host immune response with persistent lymphocyte activation represents the most convincing explanation for lymphoproliferation. Gastric MALT lymphoma is strictly associated with Helicobacter pylori infection and various eradicating protocols, developed due to increasing antibiotic resistance, represent the first line therapy for gastric MALT. The response rate to eradication is good with 80% of response at 1 year; this finding is also noteworthy because it recapitulates cancer cured only by the antibacterial approach and it satisfies the Koch postulates of causation, establishing a causative relationship between Hp and gastric MALT lymphoma. Patients with chronic HCV infection have 5 times higher risk to develop MZL, in particular, an association with splenic and nodal MZL has been shown in several studies. Moreover, there is evidence of lymphoma regression after antiviral therapy with interferon+ribavirin, thus raising hope that newly available drugs, extremely efficient against HCV replication, could improve outcome also in HCV-driven lymphomas. Another case-study are represented by those rare cases of MZL localized to orbital fat and eye conjunctivas that have been associated with Chlamydophila psittaci infection carried by birds. Efficacy of antibacterial therapy against C. psittaci are conflicting and generally poorer than gastric MALT. Finally, some case reports will cover the relationship between primary cutaneous B-cell Lymphomas and Borrelia Burgdorferi

Immunosuppression for liver transplantation in HCV-infected patients: Mechanism-based principles

We retrospectively analyzed 42 hepatitis C virus (HCV)-infected patients who underwent cadaveric liver transplantation under two strategies of immunosuppression: (1) daily tacrolimus (TAC) throughout and an initial cycle of high-dose prednisone (PRED) with subsequent gradual steroid weaning, or (2) intraoperative antithymocyte globulin (ATG) and daily TAC that was later space weaned. After 36 ± 4 months, patient and graft survival in the first group was 18/19 (94.7%) with no examples of clinically serious HCV recurrence. In the second group, the three-year patient survival was 12/23 (52%), and graft survival was 9/23 (39%); accelerated recurrent hepatitis was the principal cause of the poor results. The data were interpreted in the context of a recently proposed immunologic paradigm that is equally applicable to transplantation and viral immunity. In the framework of this paradigm, the disparate hepatitis outcomes reflected different equilibria reached under the two immunosuppression regimens between the relative kinetics of viral distribution (systemically and in the liver) and the slowly recovering HCV-specific T-cell response. As a corollary, the aims of treatment of the HCV-infected liver recipients should be to predict, monitor, and equilibrate beneficial balances between virus distribution and the absence of an immunopathologic antiviral T-cell response. In this view, favorable equilibria were accomplished in the nonweaned group of patients but not in the weaned group. In conclusion, since the anti-HCV response is unleashed when immunosuppression is weaned, treatment protocols that minimize disease recurrence in HCV-infected allograft recipients must balance the desire to reduce immunosuppression or induce allotolerance with the need to prevent antiviral immunopathology. Copyright © 2005 by the American Association for the Study of Liver Diseases

Three-dimensional architecture and biogenesis of membrane structures associated with hepatitis C virus replication

All positive strand RNA viruses are known to replicate their genomes in close association with intracellular membranes. In case of the hepatitis C virus (HCV), a member of the family Flaviviridae, infected cells contain accumulations of vesicles forming a membranous web (MW) that is thought to be the site of viral RNA replication. However, little is known about the biogenesis and three-dimensional structure of the MW. In this study we used a combination of immunofluorescence- and electron microscopy (EM)-based methods to analyze the membranous structures induced by HCV in infected cells. We found that the MW is derived primarily from the endoplasmic reticulum (ER) and contains markers of rough ER as well as markers of early and late endosomes, COP vesicles, mitochondria and lipid droplets (LDs). The main constituents of the MW are single and double membrane vesicles (DMVs). The latter predominate and the kinetic of their appearance correlates with kinetics of viral RNA replication. DMVs are induced primarily by NS5A whereas NS4B induces single membrane vesicles arguing that MW formation requires the concerted action of several HCV replicase proteins. Three-dimensional reconstructions identify DMVs as protrusions from the ER membrane into the cytosol, frequently connected to the ER membrane via a neck-like structure. In addition, late in infection multi-membrane vesicles become evident, presumably as a result of a stress-induced reaction. Thus, the morphology of the membranous rearrangements induced in HCV-infected cells resemble those of the unrelated picorna-, corona- and arteriviruses, but are clearly distinct from those of the closely related flaviviruses. These results reveal unexpected similarities between HCV and distantly related positive-strand RNA viruses presumably reflecting similarities in cellular pathways exploited by these viruses to establish their membranous replication factories

The Epidemics of Injecting Drug Use and Blood-Borne Disease: A Public Health Perspective

In this article, the author first examines the mechanism by which blood-borne disease is transmitted through sharing of injection equipment. Thereafter, he presents a public health strategy for reducing multi-person use of contaminated injection equipment. This strategy includes: repealing or modifying current laws and regulations making possession and distribution of sterile injection equipment a criminal offense; implementing syringe exchange programs to expand access to new syringes for users of injection drugs; and counseling, education, and treatment targeted to injecting drug users (IDUs), including those in the prison and health care system. The objective of a public health approach is not to encourage or enable IDUs to obtain and use drugs; public health strategies actively seek to reduce drug use due to its profound adverse effects on physical and mental health. Rather, the public health approach seeks to substantially improve health outcomes for IDUs who cannot or will not stop using drugs

Sex Hormone-Binding Globulin Levels Are Inversely Associated With Nonalcoholic Fatty Liver Disease in HIV-Infected and -Uninfected Men.

BackgroundNonalcoholic fatty liver disease (NAFLD) is a leading cause of liver disease worldwide. Elevated sex hormone-binding globulin (SHBG) levels have been observed in the setting of HIV and may protect against some metabolic disorders. We aimed to investigate whether higher SHBG levels may protect against NAFLD in men with/without HIV.MethodsNAFLD was assessed using noncontrast computed tomography in 530 men in the Multicenter AIDS Cohort Study (MACS) who drank <3 alcoholic drinks/d and were uninfected with chronic hepatitis C or B (340HIV+, 190HIV-). Morning serum samples were tested for SHBG, total testosterone (TT), and adiponectin. Multivariable logistic regression was used to assess associations between HIV, SHBG, TT, adiponectin, and NAFLD.ResultsMedian SHBG was highest among HIV+/NAFLD- men and lowest among HIV-/NAFLD+ men. Adjusted for demographics, HIV, visceral adiposity, HOMA-IR, TT, and PNPLA3 genotype, higher SHBG was associated with lower odds of NAFLD (odds ratio [OR], 0.52 per doubling; 95% confidence interval [CI], 0.34-0.80). In separate multivariable models without SHBG, HIV (OR, 0.46; 95% CI, 0.26-0.79) and higher adiponectin (OR, 0.66 per doubling; 95% CI, 0.49-0.89) were associated with lower NAFLD odds, whereas TT was not significantly associated (OR, 0.74 per doubling; 95% CI, 0.53-1.04). Adjusting for SHBG attenuated the associations of HIV (OR, 0.61; 95% CI, 0.34-1.08) and adiponectin (OR, 0.74; 95% CI, 0.54-1.02) with NAFLD.ConclusionsSHBG levels were higher among HIV+ men, were independently associated with lower NAFLD, and could partially explain the associations of HIV and higher adiponectin with lower NAFLD in our cohort. These findings suggest that SHBG may protect against NAFLD, supporting further prospective and mechanistic studies