In this study, we find that mbl2 genotypes correlating with high MBL levels are associated with recovery from an HBV infection whereas those correlating with lower levels are associated with viral persistence. The major role of MBL is activation of complement; however, complement does not play a known role in HBV pathogenesis. Thus, these data suggest either a novel mechanism of immune response to HBV involving complement or an alternative role for MBL in HBV pathogenesis.
Although direct binding of MBL to HBV has not been demonstrated, it could occur since the HBV envelope contains the required N
-acetylglucosamine and mannose recognition moieties (23
). Once bound, the precise role of MBL in clearance of HBV is not known; however, a variety of potential mechanisms are plausible. A major function of MBL is activation of the classical complement cascade through the cleavage of C4 and C2 by the MBL-associated serine protease (7
). Thus, whether complement plays a role in HBV pathogenesis deserves investigation. MBL has been associated with antiviral responses including interference in attachment of influenza A virus to host cells, viral spread, and viral release (17
). In HIV infection, MBL has been shown to bind to gp120, which prevents binding of the virus to its CD4 receptor (6
). It is possible that such mechanisms may occur with HBV. Another plausible biological role for MBL is via up- or down-regulation in cytokine production, which occurs in vitro with fungi, parasites, and bacteria (2
). The precise nature of the cytokine response is dependent upon the organism, but alteration of levels of tumor necrosis factor alpha, which is a cytokine important for noncytolytic clearance of HBV (10
), has been described. Further work is needed to determine the precise contribution of MBL to the control of HBV infection.
It is important that the results of genotype and haplotype analyses were consistent with the relationships found when individuals were grouped by presumed functional MBL levels. The −221C (X) allele and the XA haplotype were associated with viral persistence, and individuals with these genotypes were found only in groups of subjects producing intermediate or low levels of MBL. On the other hand, the YA haplotype was more common in those who recovered from hepatitis B, which is consistent with the fact that this haplotype was restricted to the groups with either high or intermediate MBL levels.
It is also notable that the ORs for the significant SNPs and SNP combinations were similar in both blacks and whites, the two major ethnic groups in this population. This consistent trend suggests that MBL is involved directly in HBV clearance rather than indirectly through linkage disequilibrium with neighboring loci.
A few other studies have examined mbl2
with respect to recovery from HBV infection, but the data are inconsistent (1
). In the largest of these studies, investigators genotyped the codon 52, 54, and 57 SNPs in 180 Gambians with persistent HBV infections and 157 who had recovered from HBV infections (1
). The frequency of the codon 57 homozygous mutant was higher in those with viral persistence (8.9% versus 5.7%) but did not reach statistical significance. The other SNPs were not present in the homozygous mutant state. Since the −221 promoter SNP was not examined in this study, the investigators could not analyze the YA/YA
genotype. Differences between studies may also be related to the age of subjects at HBV acquisition. In The Gambia, transmission of HBV generally occurs in early childhood (34
), whereas in the United States, acquisition is usually in adulthood. Since children are more likely to have viral persistence after HBV infection (20
), different aspects of the immune system may be relatively more important depending on whether HBV was acquired before or during adulthood. Of the other studies, one found an association between the codon 52 mutation and HBV persistence (31
It would have been helpful to be able to correlate the precise levels of MBL in these subjects with the MBL genotypes and HBV infection outcomes. However, since MBL is an acute-phase reactant, the levels in sera when subjects were enrolled in this study would not be expected to be representative of levels at the time when HBV persistence or recovery from infection was determined. In addition, the fact that persons with chronic hepatitis B have an ongoing infection would serve as a strong confounder in a posthoc evaluation of MBL levels. A meaningful measurement of MBL levels in our cohort would require a sample taken prior to HBV infection, which is not available. Fortunately, there is a well-established relationship between genotypes and MBL levels, as has been documented for over 1,000 individuals (8
Approximately half of our subjects were HIV infected, but this could not have affected the results of our study for several reasons. HBV infection occurs prior to HIV infection in most cases, so the outcome of the viral hepatitis infection is determined prior to acquisition of HIV (19
). Even more convincingly, those recovered from infection and those with viral persistence were matched according to HIV infection status, and stratification of results of the analysis with respect to HIV infection status did not significantly alter the results.
In summary, this is the first study to clearly demonstrate that genetically determined differences in mbl2 are important determinants of recovery from HBV infection. These data support the importance of the innate immune response in this process, but further study is needed to explain the precise role of MBL in HBV pathogenesis.