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Principal Investigator: ALAN S PERELSON
Organization: LOYOLA UNIVERSITY CHICAGO
Fiscal Year: 2024
Award: $632,809
Funding agency: National Institute of Allergy and Infectious Diseases
Hepatitis C virus (HCV) is a hepatotropic virus that establishes chronic infection in ~70% of those exposed. As
a result, currently more than 71 million people worldwide are infected and at increased risk of developing liver
disease and hepatocellular carcinoma. While effective interferon (IFN)-free direct acting antiviral (DAA)
therapeutic combinations are highly potent, the promise of DAAs has not yet put us on track to achieve the WHO
goal of elimination by 2030. Reaching this goal will require a scaling-up of HCV screening, linkage-to-care, and
reduction of treatment cost. Additionally, this will require understanding HCV spread, specifically how to prevent
the spread of viral antiviral resistance variants within individuals such that these drug resistance viruses are not
transmitted to the population. Importantly, viral cell-to-cell spread has been implicated in antiviral escape,
immune escape, and persistence of viruses in general. Thus, the insights gained through the study of HCV
should broadly inform future antiviral strategies.
Mathematical modeling of HCV in the serum of infected patients during therapy has driven our understanding of
HCV infection dynamics, the effect of IFN treatment, and led to methods for the quantitative evaluation of HCV
treatment efficacy. Since FDA-approval of HCV DAAs, we have pioneered the development of multiscale models
of DAA treatment response in vitro and in patients. This work revealed the dual mechanism of action of NS5A
inhibitors and has demonstrated that viral kinetic modeling might allow for a reduction in the duration of DAA
therapy in the majority of patients. These clinical insights have been informed by our modeling of HCV infection
in cell culture where we are able to directly measure both intracellular and extracellular viral and cellular
parameters. Applying both cell culture experimentation and in vivo patient data, we have recently obtained
evidence that viral entry/spread plays a major role in the maintenance of steady state infection having broad
implications regarding viral spread as an antiviral drug target and how spread impacts antiviral treatment
response in terms of drug efficacy, viral escape, and drug synergy.
Because these new models have raised important biological questions about HCV spread and antiviral drug
strategies, the objective of this cross disciplinary R01 renewal is to enable the improvement of the treatment for
HCV and other viruses by formulating and testing mathematical models of HCV infection and treatment response
in vivo and in vitro. The specific aims are: 1) Refine and validate time to cure predictions using in vivo and in
silico trials; 2) Elucidate quantitative details about the HCV life cycle and the role of hepatocytes in HCV
clearance; 3) Expand and optimize mathematical models of HCV cell-to-cell spread; and 4) Determine the
importance of cell-to-cell spread as an antiviral drug target.
Terms: <Accounting><Address><Anti-viral Agents><Anti-viral Therapy><Anti-viral resistance><Award><Biological><Biological Function><Biological Process><Blood Serum><Caring><Cell Body><Cell Culture Techniques><Cells><Chronic><Cirrhosis><Clinical><Data><Development><Drug Synergism><Drug Targeting><Drug resistance><Drugs><Ebola><Effectiveness><Fatty Liver><Fibrosis><Fostering><Funding><Future><Goals><Grant><HCV><HCV Cirrhosis><HCV infection><HCV screening><HCV therapy><HCV treatment><Hepatic Cells><Hepatic Disorder><Hepatic Parenchymal Cell><Hepatitis C><Hepatitis C Therapeutics><Hepatitis C Therapy><Hepatitis C Virus Treatment><Hepatitis C treatment><Hepatitis C virus><Hepatitis C virus infection><Hepatitis C virus screening><Hepatitis, Viral, Non-A, Non-B, Parenterally-Transmitted><Hepatitus C><Hepatocarcinoma><Hepatocellular Carcinoma><Hepatocellular cancer><Hepatocyte><Hepatoma><IFN><Immune><Immunes><In Vitro><Individual><Infection><Inflammation><Insulin Resistance><Interferons><Knowledge><Life Cycle><Life Cycle Stages><Liver Cells><Liver Cells Carcinoma><Liver Steatosis><Liver diseases><Maintenance><Math><Math Models><Mathematics><Measures><Medication><Methods><Modeling><Molecular><Molecular Virology><NIH RFA><Patients><Persons><Pharmaceutical Preparations><Play><Population><Primary carcinoma of the liver cells><Public Health><Quantitative Evaluations><RNA Viruses><RNA replication><Request for Applications><Risk><Role><SARS><SARS coronavirus disease><SARS-CoV disease><Serum><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome coronavirus disease><System><Testing><Therapeutic><Time><Treatment Cost><Treatment Efficacy><United States><Variant><Variation><Viral><Virus><Work><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral resistant><anti-viral therapeutic><anti-virals><biologic><cell culture><cell cultures><chronic infection><cirrhotic><clinical relevance><clinically relevant><combat><cost><customized therapy><customized treatment><design><designing><developmental><drug efficacy><drug resistant><drug/agent><emergent virus><emerging virus><experience><extracellular><hep C><hepatic disease><hepatic steatosis><hepatitis C virus cirrhosis><hepatitis non A non B><hepatopathy><hepatosteatosis><high risk group><high risk individual><high risk people><high risk population><improved><in silico><in vivo><individualized medicine><individualized patient treatment><individualized therapeutic strategy><individualized therapy><individualized treatment><infection by hepatitis c virus><inhibitor><insight><insulin resistant><insulin tolerance><intervention efficacy><kinetic model><life course><liver carcinoma><liver disorder><mathematic model><mathematical model><mathematical modeling><multi-scale computational modeling><multi-scale mathematical modeling><multi-scale modeling><multiscale computational modeling><multiscale mathematical modeling><multiscale modeling><non A, non B hepatitis><non-A, non-B hepatitis><patient specific therapies><patient specific treatment><persistent infection><prevent><preventing><resistance to Drug><resistant to Drug><response to therapy><response to treatment><scale up><social role><tailored medical treatment><tailored therapy><tailored treatment><therapeutic efficacy><therapeutic response><therapy duration><therapy efficacy><therapy response><tool><treatment effect><treatment response><treatment responsiveness><unique treatment><viral RNA><viral emergence><viral infectious disease treatment><viral resistance><virus RNA><virus resistance>