Chance and necessity of simultaneous HBsAg and anti-HBs detection in the serum of chronic HBsAg carriers

摘要

Patients who recover from acute hepatitis B clear surface antigen (HBsAg) from serum and anti-HBs becomes detectable as hallmark of HBV immune control. However, anti-HBs appear weeks after HBsAg clearance and neutralizing antibodies are unlikely to contribute to early viral control but to prevent viral spread from cells that remain infected after hepatitis resolution [1]. This notion is supported by the evidence that chimpanzees resolving hepatitis B are protected from viral rechallenge [2]. Similarly, in non-infected individuals an adequate anti-HBs production (>10mUI/ml) indicates a protective immunity after vaccination [1]. Several evidences suggest that anti-HBs are present also in chronic HBsAg carriers, but not detected because hidden in circulating immune-complexes [3]. Thus the simultaneous detection of HBsAg/anti-HBs (HBsAg/anti-HBs-co-detection) represents an atypical serologic profile puzzling virologists and clinicians since the late 1970s [3-5]. Initially, it was explained by heterologous antibodies against subtypes different from the infecting HBV subtype, as HBsAg subtypes dy infections could associate with y/d anti-HBs subtypes [6]. The hypothesis of primary infection with 2 subtypes followed by clearance of only one of them was contradicted by the animal model where humoral response against the a determinant of HBsAg prevented the re-infection with different HBV subtypes [3]. In addition, ay anti-HBs was found in HBsAg carriers from Japan, where this subtype is uncommon [7]. Therefore, the hypothesis of a mixed infection was dismissed in favour of clonal selection of antibody diversity [3]. The high similarity between 2 HBV serotypes (i.e., HBsAg/ad and HBsAg/ ay) could induce the clonal expansion not only of high-titre, high-affinity anti-a and anti-d, but also lower-titre, low-affinity heterotypic anti-y [3,4]. Nevertheless, the question remains why only a minority of HBsAg carriers exhibit this condition. After the introduction of molecular biology techniques the characterization of viral quasispecies in clinical settings of HBV infections despite vaccination or HBIg treatment showed that HBsAg/anti-HBs-co-detection was associated with viral strains carrying HBsAg mutations that escaped the anti-HBs neutralization [8,9]. These findings raise the question whether genetic