scholarly journals Mathematical Analysis of the Role of HIV/HBV Latency in Hepatocytes

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Hasifa Nampala ◽  
Matylda Jablonska-Sabuka ◽  
Martin Singull
Keyword(s):  
Optimal Control ◽  
Viral Latency ◽  
Latency Period ◽  
Viral Reservoirs ◽  
Optimal Control Strategy ◽  
Analytical Results ◽  
Latently Infected ◽  
Infected Cells ◽  
Cd4 Cell ◽  
The Impact

The biggest challenge of treating HIV is rampant liver-related morbidity and mortality. This is, to some extent, attributed to hepatocytes acting as viral reservoirs to both HIV and HBV. Viral reservoirs harbour latent provirus, rendering it inaccessible by combinational antiretroviral therapy (cART) that is specific to actively proliferating virus. Latency reversal agents (LRA) such as Shock and kill or lock and block, aiming at activating the latently infected cells, have been developed. However, they are CD4+ cell-specific only. There is evidence that the low replication level of HIV in hepatocytes is mainly due to the latency of the provirus in these cells. LRA are developed to reduce the number of latently infected cells; however, the impact of the period viral latency in hepatocytes especially, during HIV/HBV coinfection, needs to be investigated. Viral coinfection coupled with lifelong treatment of HIV/HBV necessitates investigation for the optimal control strategy. We propose a coinfection mathematical model with delay and use optimal control theory to analyse the effect of viral latency in hepatocytes on the dynamics of HIV/HBV coinfection. Analytical results indicate that HBV cannot take a competitive exclusion against HIV; thus, the coinfection endemic equilibrium implies chronic HBV in HIV-infected patients. Numerical and analytical results indicate that both HIV and HBV viral loads are higher with longer viral latency period in hepatocytes, which indicates the need to upgrade LRA to other non-CD4+ cell viral reservoirs. Higher viral load caused by viral latency coupled with the effects of cART partly explains why liver-related complications are the leading cause of mortality in HIV-infected persons.

scholarly journals The gammaherpesvirus 68 viral cyclin facilitates reactivation by promoting latent gene expression

2019 ◽  
Author(s):  
Brian F Niemeyer ◽  
Joy E Gibson ◽  
Jennifer N Berger ◽  
Lauren M Oko ◽  
Eva Medina ◽  
...  
Keyword(s):  
Gene Expression ◽  
Critical Role ◽  
Productive Infection ◽  
Viral Gene ◽  
Cellular Distribution ◽  
Viral Cyclin ◽  
Latently Infected ◽  
Infected Cells ◽  
Virally Encoded ◽  
The Impact

AbstractGammaherpesviruses establish life-long infections within their host and have been shown to be the causative agents of devastating malignancies. Chronic infection within the host is mediated through cycles of transcriptionally quiescent stages of latency with periods of reactivation into more active lytic and productive infection. The mechanisms that regulate reactivation from latency remain poorly understood. Previously, we defined a critical role for the viral cyclin in promoting reactivation from latency. Disruption of the viral cyclin had no impact on the frequency of cells containing viral genome during latency, yet it remains unclear whether the viral cyclin influences latently infected cells in a qualitative manner. To define the impact of the viral cyclin on latent gene expression, we utilized a viral cyclin deficient variant expressing a LANA-beta-lactamase fusion protein (LANA::βla), to enumerate both the cellular distribution and frequency of latent gene expression. Disruption of the viral cyclin did not affect the cellular distribution of latently infected cells, but did result in a significant decrease in the frequency of cells that expressed LANA::βla across multiple tissues and in both immunocompetent and immunodeficient hosts. Strikingly, whereas the cyclin-deficient virus had a reactivation defect in bulk culture, sort purified cyclin-deficient LANA::βla expressing cells were fully capable of reactivation. These data emphasize that the γHV68 latent reservoir is comprised of at least two distinct stages of infection characterized by differential latent gene expression, and that a primary function of the viral cyclin is to promote latent gene expression within infected cells in vivo.AUTHOR SUMMARYGammaherpesviruses are ubiquitous viruses with oncogenic potential that establish latency for the life of the host. These viruses can emerge from latency through reactivation, a process that is controlled by the immune system. Control of viral latency and reactivation is thought to be critical to prevent γHV-associated disease. This study focuses on a virally-encoded cyclin that is required for reactivation from latency. By characterizing how the viral cyclin influences latent infection in pure cell populations, we find that the viral cyclin has a vital role in promoting viral gene expression during latency. This work provides new insight into the function of a virally encoded cyclin in promoting reactivation from latency.

scholarly journals Bifurcation analysis and optimal control of SEIR epidemic model with saturated treatment function on the network

2021 ◽  
Vol 19 (2) ◽  
pp. 1677-1695
Author(s):  
Boli Xie ◽  
◽  
Maoxing Liu ◽  
Lei Zhang
Keyword(s):  
Optimal Control ◽  
Disease Transmission ◽  
Equilibrium Points ◽  
Virus Transmission ◽  
Population Heterogeneity ◽  
Multiple Equilibrium ◽  
Optimal Control Strategy ◽  
Treatment Function ◽  
The Stability ◽  
The Impact

<abstract><p>In order to study the impact of limited medical resources and population heterogeneity on disease transmission, a SEIR model based on a complex network with saturation processing function is proposed. This paper first proved that a backward bifurcation occurs under certain conditions, which means that $ R_{0} &lt; 1 $ is not enough to eradicate this disease from the population. However, if the direction is positive, we find that within a certain parameter range, there may be multiple equilibrium points near $ R_{0} = 1 $. Secondly, the influence of population heterogeneity on virus transmission is analyzed, and the optimal control theory is used to further study the time-varying control of the disease. Finally, numerical simulations verify the stability of the system and the effectiveness of the optimal control strategy.</p></abstract>

Dynamical analysis of a class of hepatitis C virus infection models with application of optimal control

2016 ◽  
Vol 09 (03) ◽  
pp. 1650038 ◽  
Author(s):  
Aida Mojaver ◽  
Hossein Kheiri
Keyword(s):  
Optimal Control ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Deterministic Model ◽  
Treatment Strategies ◽  
Dynamical Analysis ◽  
Existence And Stability ◽  
Direct Cell ◽  
Infected Cells ◽  
The Impact

In this paper, we deal with the problem of optimal control of a deterministic model of hepatitis C virus (HCV). In the first part of our analysis, a mathematical modeling of HCV dynamics which can be controlled by antiretroviral therapy as fixed controls has been presented and analyzed which incorporates two mechanisms: infection by free virions and the direct cell-to-cell transmission. Basic reproduction number is calculated and the existence and stability of equilibria are investigated. In the second part, the optimal control problem representing drug treatment strategies of the model is explored considering control parameters as time-dependent in order to minimize not only the population of infected cells but also the associated costs. At the end of the paper, the impact of combination of the strategies in the control of HCV and their effectiveness are compared by numerical simulation.

scholarly journals The Impact of Cellular Proliferation on the HIV-1 Reservoir

Viruses ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 127
Author(s):  
Maria C. Virgilio ◽  
Kathleen L. Collins
Keyword(s):  
Cellular Proliferation ◽  
Integration Site ◽  
Infected Individual ◽  
Host Cells ◽  
Viral Reservoir ◽  
Proliferative Potential ◽  
Proliferation And Differentiation ◽  
Latently Infected ◽  
Infected Cells ◽  
The Impact

Human immunodeficiency virus (HIV) is a chronic infection that destroys the immune system in infected individuals. Although antiretroviral therapy is effective at preventing infection of new cells, it is not curative. The inability to clear infection is due to the presence of a rare, but long-lasting latent cellular reservoir. These cells harboring silent integrated proviral genomes have the potential to become activated at any moment, making therapy necessary for life. Latently-infected cells can also proliferate and expand the viral reservoir through several methods including homeostatic proliferation and differentiation. The chromosomal location of HIV proviruses within cells influences the survival and proliferative potential of host cells. Proliferating, latently-infected cells can harbor proviruses that are both replication-competent and defective. Replication-competent proviral genomes contribute to viral rebound in an infected individual. The majority of available techniques can only assess the integration site or the proviral genome, but not both, preventing reliable evaluation of HIV reservoirs.

scholarly journals Latent Antigen Vaccination in a Model Gammaherpesvirus Infection

2001 ◽  
Vol 75 (17) ◽  
pp. 8283-8288 ◽  
Author(s):  
Edward J. Usherwood ◽  
Kimberley A. Ward ◽  
Marcia A. Blackman ◽  
James P. Stewart ◽  
David L. Woodland
Keyword(s):  
Latent Infection ◽  
Model Systems ◽  
Murine Gammaherpesvirus ◽  
Latently Infected ◽  
Associated Proteins ◽  
Infected Cells ◽  
The Impact ◽  
First Time

ABSTRACT Vaccines that can reduce the load of latent gammaherpesvirus infections are eagerly sought. One attractive strategy is vaccination against latency-associated proteins, which may increase the efficiency with which T cells recognize and eliminate latently infected cells. However, due to the lack of tractable animal model systems, the effect of latent-antigen vaccination on gammaherpesvirus latency is not known. Here we use the murine gammaherpesvirus model to investigate the impact of vaccination with the latency-associated M2 antigen. As expected, vaccination had no effect on the acute lung infection. However, there was a significant reduction in the load of latently infected cells in the initial stages of the latent infection, when M2 is expressed. These data show for the first time that latent-antigen vaccination can reduce the level of latency in vivo and suggest that vaccination strategies involving other latent antigens may ultimately be successfully used to reduce the long-term latent infection.

scholarly journals Modeling the Impact of Optimal Control Strategies on the Dynamics of Zika Virus Disease Using the Sterile Insect Technology

2020 ◽  
pp. 13-33
Author(s):  
Atokolo William ◽  
Akpa Johnson ◽  
Daniel Musa Alih ◽  
Olayemi Kehinde Samuel ◽  
C. E. Mbah Godwin
Keyword(s):  
Optimal Control ◽  
Control Strategy ◽  
Zika Virus ◽  
Human Population ◽  
Necessary Conditions ◽  
Virus Disease ◽  
Control Strategies ◽  
Control Measures ◽  
Optimal Control Strategy ◽  
The Impact

This work is aimed at formulating a mathematical model for the control of zika virus infection using Sterile Insect Technology (SIT). The model is extended to incorporate optimal control strategy by introducing three control measures. The optimal control is aimed at minimizing the number of Exposed human, Infected human and the total number of Mosquitoes in a population and as such reducing contacts between mosquitoes and human, human to human and above all, eliminates the population of Mosquitoes. The Pontryagin’s maximum principle was used to obtain the necessary conditions, find the optimality system of our model and to obtain solution to the control problem. Numerical simulations result shows that; reduction in the number of Exposed human population, Infected human population and reduction in the entire population of Mosquito population is best achieved using the optimal control strategy.

scholarly journals Identification of Infected B-Cell Populations by Using a Recombinant Murine Gammaherpesvirus 68 Expressing a Fluorescent Protein

2009 ◽  
Vol 83 (13) ◽  
pp. 6484-6493 ◽  
Author(s):  
Christopher M. Collins ◽  
Jeremy M. Boss ◽  
Samuel H. Speck
Keyword(s):  
B Cells ◽  
Virus Infection ◽  
Plasma Cells ◽  
Fluorescent Protein ◽  
Viral Latency ◽  
Murine Gammaherpesvirus ◽  
Latently Infected ◽  
Infected Cells ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

ABSTRACT Infection of inbred mice with murine gammaherpesvirus 68 (MHV68) has proven to be a powerful tool to study gammaherpesvirus pathogenesis. However, one of the limitations of this system has been the inability to directly detect infected cells harvested from infected animals. To address this issue, we generated a transgenic virus that expresses the enhanced yellow fluorescent protein (YFP), driven by the human cytomegalovirus immediate-early promoter and enhancer, from a neutral locus within the viral genome. This virus, MHV68-YFP, replicated and established latency as efficiently as did the wild-type virus. During the early phase of viral latency, MHV68-YFP efficiently marked latently infected cells in the spleen after intranasal inoculation. Staining splenocytes for expression of various surface markers demonstrated the presence of MHV68 in distinct populations of splenic B cells harboring MHV68. Notably, these analyses also revealed that markers used to discriminate between newly formed, follicular and marginal zone B cells may not be reliable for phenotyping B cells harboring MHV68 since virus infection appears to modulate cell surface expression levels of CD21 and CD23. However, as expected, we observed that the overwhelming majority of latently infected B cells at the peak of latency exhibited a germinal center phenotype. These analyses also demonstrated that a significant percentage of MHV68-infected splenocytes at the peak of viral latency are plasma cells (ca. 15% at day 14 and ca. 8% at day 18). Notably, the frequency of virus-infected plasma cells correlated well with the frequency of splenocytes that spontaneously reactivate virus upon explant. Finally, we observed that the efficiency of marking latently infected B cells with the MHV68-YFP recombinant virus declined at later times postinfection, likely due to shut down of transgene expression, and indicating that the utility of this marking strategy is currently limited to the early stages of virus infection.

scholarly journals Total HIV-1 DNA, a Marker of Viral Reservoir Dynamics with Clinical Implications

2016 ◽  
Vol 29 (4) ◽  
pp. 859-880 ◽  
Author(s):  
Véronique Avettand-Fènoël ◽  
Laurent Hocqueloux ◽  
Jade Ghosn ◽  
Antoine Cheret ◽  
Pierre Frange ◽  
...  
Keyword(s):  
Cell Count ◽  
Cell Activation ◽  
Viral Reservoirs ◽  
Hiv Pathogenesis ◽  
Cd4 Cell Count ◽  
Hiv Rna ◽  
Hiv Dna ◽  
Infected Cells ◽  
Cd4 Cell ◽  
Hiv 1

SUMMARYHIV-1 DNA persists in infected cells despite combined antiretroviral therapy (cART), forming viral reservoirs. Recent trials of strategies targeting latent HIV reservoirs have rekindled hopes of curing HIV infection, and reliable markers are thus needed to evaluate viral reservoirs. Total HIV DNA quantification is simple, standardized, sensitive, and reproducible. Total HIV DNA load influences the course of the infection and is therefore clinically relevant. In particular, it is predictive of progression to AIDS and death, independently of HIV RNA load and the CD4 cell count. Baseline total HIV DNA load is predictive of the response to cART. It declines during cART but remains quantifiable, at a level that reflects both the history of infection (HIV RNA zenith, CD4 cell count nadir) and treatment efficacy (residual viremia, cumulative viremia, immune restoration, immune cell activation). Total HIV DNA load in blood is also predictive of the presence and severity of some HIV-1-associated end-organ disorders. It can be useful to guide individual treatment, notably, therapeutic de-escalation. Although it does not distinguish between replication-competent and -defective latent viruses, the total HIV DNA load in blood, tissues, and cells provides insights into HIV pathogenesis, probably because all viral forms participate in host cell activation and HIV pathogenesis. Total HIV DNA is thus a biomarker of HIV reservoirs, which can be defined as all infected cells and tissues containing all forms of HIV persistence that participate in pathogenesis. This participation may occur through the production of new virions, creating new cycles of infection and disseminating infected cells; maintenance or amplification of reservoirs by homeostatic cell proliferation; and viral transcription and synthesis of viral proteins without new virion production. These proteins can induce immune activation, thus participating in the vicious circle of HIV pathogenesis.

Optimal vaccination policy and cost analysis for epidemic control in resource-limited settings

Kybernetes ◽  
2015 ◽  
Vol 44 (3) ◽  
pp. 475-486 ◽  
Author(s):  
Kuan Yang ◽  
Ermei Wang ◽  
Yinggao Zhou ◽  
Kai Zhou
Keyword(s):  
Optimal Control ◽  
Control Strategy ◽  
Mass Action ◽  
Sir Epidemic Model ◽  
Epidemic Control ◽  
Optimal Control Strategy ◽  
Content Type ◽  
Total Cost ◽  
Time Optimal ◽  
The Impact

Purpose – The purpose of this paper is to use analytical method and optimization tools to suggest time-optimal vaccination program for a basic SIR epidemic model with mass action contact rate when supply is limited. Design/methodology/approach – The Lagrange Multiplier Method and Pontryagin’s Maximum Principle are used to explore optimal control strategy and obtain analytical solution for the control system to minimize the total cost of disease with boundary constraint. The numerical simulation is done with Matlab using the sequential linear programming method to illustrate the impact of parameters. Findings – The result highlighted that the optimal control strategy is Bang-Bang control – to vaccinate with maximal effort until either all of the resources are used up or epidemic is over, and the optimal strategies and total cost of vaccination are usually dependent on whether there is any constraint of resource, however, the optimal strategy is independent on the relative cost of vaccination when the supply is limited. Practical implications – The research indicate a practical view that the enhancement of daily vaccination rate is critical to make effective initiatives to prevent epidemic from out breaking and reduce the costs of control. Originality/value – The analysis of the time-optimal application of outbreak control is of clear practical value and the introducing of resource constraint in epidemic control is of realistic sense, these are beneficial for epidemiologists and public health officials.

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