From the Journals

Small study suggests natural HCV clearance is caused by AR3-antibody response



Individuals who spontaneously cleared their primary hepatitis C virus (HCV) infection or reinfection had significantly more antibodies that recognized multiple HCV genotypes beyond the initial infection, compared with chronically infected individuals, according to a small molecular study of immortalized cultured B cells from patient.

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In a study published in the Journal of Hepatology, Sabrina J. Merat of AIMM Therapeutics and colleagues classified patients into two groups based on the outcome of their HCV infection: individuals who became chronically infected (CHRs; n = 5) either after primary infection or after HCV reinfection and individuals who cleared one or more HCV infections and were HCV RNA negative at the end of follow-up (CLs; n = 8). The researchers considered that all CLs who cleared the infection were presumably re-exposed to HCV as they continued injecting drugs for a median of 5.9 years after primary infection. The median follow-up time of individuals after primary HCV infection was 17.5 years.

Although the frequency of total antibodies did not differ between the two groups, the antibodies from CHRs were mainly genotype specific and directed against the genotype of the ongoing infection. Antibodies from CLs showed a much broader reactivity than CHR-derived antibodies, with the absolute number of antibodies recognizing at least three or more genotypes was significantly higher in CLs than in CHRs (13 vs. 0, respectively; P = .03).

In addition, in order to determine which epitopes were being targeted in the CL patients, the researchers tested the antibodies secreted in the B-cell supernatant for binding to E2 alanine mutants in the four epitopes known to be recognized by broadly neutralizing HCV antibodies. They found that the majority of the cross-genotype antibodies (82/113; 73%) were specific for AR3 because they bound to the AR3-specific mutants.

“In chronically infected individuals, AR3-specific antibody responses may be too weak and/or may develop too late to prevent chronic infection. If confirmed, this means that a strong and broadly neutralizing antibody response should be established very early after infection in order to confer protection,” the researchers concluded.

This study was supported by the Virgo consortium, funded by the Dutch government. Sabrina Merat and several coauthors are employees of AIMM Therapeutics, as well as shareholders.

SOURCE: Merat SJ et al. J Hepatol 2019;71:14-24.

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