Thedynamics ofhepatitis B virus infection

Weconsider acellular modelofinfection by thehepatitis B virus anddescribe howitmaybeusedto account fortwoimportant features ofthedisease, namely (i) thewidevariety ofmanifestations ofinfection andtheage dependence thereof, and(ii) thetypically longdelay before the development ofvirus-induced liver cancer (primary hepato- cellular carcinoma). Themodelisbasedontheassumption thattheliver iscomprised ofbothimmature andmature hepatocytes, withthese twosubpopulations ofcells responding contrastingly uponinfection bythevirus. Although replication ofthehepatitis B virus (HBV)isonly weakly cytopathic toward thehostcell, HBV infection is nonetheless themajorcause ofliver disease inman(1). The extent ofthesuffering caused bythevirus isaconsequence not just ofits high prevalence, there being anestimated 300million carriers worldwide, butalso ofthevariety ofdifferent clinical manifestations that canresult frominfection. Disease inadults usually leads torecovery andimmunity, mostcommonly subsequent toacute hepatitis, butalsosometimes following subclinical infection (2); whereas ifthehepatitis B virus surface antigen (HBsAg), whichcanbedetected eveninthe absence ofactive replication, hasnotbeencleared within 6 months, thedisease istermed chronic andinfection islikely to persist. Theprogression toachronic carrier state isage- dependent, being commonininfants, occasional inchildren, andrareinadults (3,4).Persistent infection maybeeither asymptomatic orsymptomatic-the meanageofasymptom- atic carriers islower thanthat ofsymptomatic carriers (5)- andcanlead tovarious outcomes, including chronic persistent hepatitis, chronic active hepatitis, andpostnecrotic cirrhosis (6). Some25-50%ofcarriers goontodevelop primary hepatocellular carcinoma (PHC), typically around 30-50 years after initial infection (7,8).Thedestruction ofinfected hepatocytes isbelieved tobeaconsequence ofthehost's immuneresponses, andprimarily results fromtheaction of cytotoxic T cells (9,10). Inthis report wedescribe howasimple cellular model forthe pathogenesis ofHBV maybeusedtoaccount forthevariety ofmanifestations ofinfection, theoutcome depending only on theageandimmunological status ofthepatient. Inaddition, themodelprovides anexplanation forvarious features ofthe relationship between HBV andPHC,including apossible dynamical explanation forthecharacteristic long delay before theonset ofvirally-induced neoplasms.