Multiscale modeling of HBV infection integrating intra- and intercellular viral propagation to analyze extracellular viral markers

Chronic infection with hepatitis B virus (HBV) is caused by the persistence of closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. Despite available therapeutic anti-HBV agents, eliminating the cccDNA remains challenging. Thus, quantifying and understanding the dynamics of cccDNA are essential for developing effective treatment strategies and new drugs. However, such study requires repeated liver biopsy to measure the intrahepatic cccDNA, which is basically not accepted because liver biopsy is potentially morbid and not common during hepatitis B treatment. We here aimed to develop a noninvasive method for quantifying cccDNA in the liver using surrogate markers in peripheral blood. We constructed a multiscale mathematical model that explicitly incorporates both intracellular and intercellular HBV infection processes. The model, based on age-structured partial differential equations, integrates experimental data from in vitro and in vivo investigations. By applying this model, we roughly predicted the amount and dynamics of intrahepatic cccDNA within a certain range using specific viral markers in serum samples, including HBV DNA, HBsAg, HBeAg, and HBcrAg. Our study represents a significant step towards advancing the understanding of chronic HBV infection. The noninvasive quantification of cccDNA using our proposed method holds promise for improving clinical analyses and treatment strategies. By comprehensively describing the interactions of all components involved in HBV infection, our multiscale mathematical model provides a valuable framework for further research and the development of targeted interventions.Author summary: In viral infectious diseases, evaluating the quantity and dynamics of the virus within target cells is crucial for understanding disease progression caused by the virus and predicting the efficacy of anti-viral drugs. HBV, which infects the human liver, increases the risk of development of hepatocellular carcinoma with chronic infection. To avoid the risk, viral elimination by anti-viral treatment is needed. The final goal of HBV treatment is the elimination of cccDNA known as a viral reservoir, although it is challenging with current treatment. One of the barriers to this lies in the fact that cccDNA remains within the liver without entering the peripheral blood, making it difficult to assess the quantity and dynamics of cccDNA within the patient. To quantitate cccDNA, an invasive method called liver biopsy is necessary. This method involves inserting a large needle through the abdomen into the liver, which is basically not accepted. In this study, we constructed a multiscale mathematical model based on the experimental data, which allowed us to evaluate the quantity and dynamics of cccDNA using viral markers in the peripheral blood, if the baseline cccDNA amount prior to treatment has been quantified. The method we have developed is expected to significantly contribute to the improvement of future HBV treatment strategies.