Anna Pinson

Introduction. Hepatitis B Virus (HBV) affects 240 million individuals worldwide.¹ While vaccines are readily available that almost completely prevent all cases of the virus, many areas of the world do not have access to these vaccines. Many mothers with HBV will pass the disease onto their children, where it is likely to manifest as chronic HBV.² Chronic HBV is a lifelong condition that, if left untreated, leads to cirrhosis and hepatocarcinoma in 40% and 30% of cases, respectively.¹ While current antiretroviral therapies are somewhat successful at suppressing these outcomes, more research is being done to understand the mechanisms of HBV infection and preservation in the liver. One aspect of the immune response to HBV, the mitochondrial anti-viral signaling protein (MAVS). When exposed to viral DNA, this protein binds to the retinoic acid inducible gene I (RIG-I).³ This interaction causes an aggregation of MAVS at the mitochondrial membrane and downstream signaling of IFN-β and IL-6.^3,4 Methods. Recent research efforts focus heavily on the MAVS protein and conditions surrounding its function or lack thereof. There are a number of molecules, both endogenous to hepatocytes and exogenous in the HBV genome, that have been found to disrupt this vital MAVS-RIG-I interaction. In one study, cultured hepatocytes were treated with glucose to promote anaerobic conditions for HBV infection.³ In other studies, the endogenous proteins NLRX1 and ADAR1 were knocked out in transfection vectors for hepatocytes and the effects on HBV infection observed.^4,5 Finally, protein X of the HBV genome was overexpressed in hepatocytes to assess its role in MAVS-RIG-I interactions.⁶ Results. In each of the experiments described above, MAVS-RIG-I interactions were inhibited and downstream immune molecule expression was decreased. Lactate produced in anaerobic conditions sequestered MAVS and inhibited downstream signaling.³ NLRX1 and ADAR1 both inhibited MAVS.^4,5 Protein X inhibited MAVS-RIG-I in some strains of HBV.⁶ Overall, these experiments showed that in-vitro­ models for MAVS inhibition weakened the immune response and allowed further infection of HBV. Conclusions. It is possible that the research surrounding MAVS-RIG-I interactions could lead scientists to therapies that focus on making hepatocytes less amenable to HBV infection. Strategies that decreased lactate production, downregulated endogenous protein expression of NLRX1 and ADAR1, or destroyed mRNA for protein X would all theoretically work to decrease the success of HBV in its chronic infection phase. As our knowledge of HBV grows, it is promising to see potential therapeutic targets arise at the molecular level.

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