Differential effect of interferon therapy on hepatitis C virus
1B quasispecies in the non-structural 5A gene.
Recently we reported a close correlation between the degree of
mutations in the amino acid residues 2209 to 2248 of the
non-structural protein 5A gene (NS5A:2209-2248) of HCV-1b and the
response to interferon therapy. The aim of this study is to
elucidate the significance of NS5A:2209-2248 quasispecies in
therapeutic failure with interferon.
Methods. Sequential changes in NS5A:2209-2248 quasispecies were
compared before and just after interferon therapy (total dose
240-800MU), for 20 patients with chronic hepatitis related to
HCV-1b, who did not respond to interferon. The amino acid sequences
of major quasispecies were determined with direct sequencing of HCV
genome amplified by nested-PCR. The populational changes of
quasispeceis were evaluated with cloning of PCR products in 7
patients including 5 non-responders and 2 complete responders.
Amino acid sequences of the NS5A:2209-2248 with 4 to 9
substitutions compared to the prototype HCV-J were defined as
mutant type, those with 1 to 3 mutations as intermediate type, and
those with identical sequence to HCV-J as wild type.
Results. By direct sequencing, the major quasispecies was
invariably the wild type before and after therapy in 10 patients.
In 9 patients, it was the intermediate type before therapy, but it
changed to the wild type in 5 patients after therapy, and remained
the intermediate type in other 4 patients. In one patient, the
major quasispecies was the mutant type before therapy but changed
to the intermediate type after therapy. Thus, the number of amino
acid substitutions in NS5A:2209-2248 significantly decreased after
therapy (median 1 to 0, p=0.0235). By the analysis of cloned PCR
products, the population of NS5A quasispieces were heterogeneous in
each patient before therapy. In 5 non-responders, the quasispecies
with the smaller number of amino acid substitutions in
NS5A:2209-2248 were preferentially selected after therapy.
Meanwhile, 2 complete responders had solely quasispecies with three
or more amino acid substitutions before therapy, all of which were
eradicated by interferon.
Conclusion. HCV detected in sera after interferon therapy has
less amino acid substitutions in NS5A:2209-2248 than those detected
before therapy. Such interferon resistant HCV had already existed
before therapy as minor quasispecies in non-responders, and were
selected by interferon resulting in the therapeutic failure.
From: American Gastroenterology Association Digestive Disease
Week meeting in Washington in May 1997
I.Sakuma, N.Enomoto, Y.Asahina, M.Kurosaki, F.Marumo, C.Sato.
Second Department of Internal Medicine and Division of Health
Science, Tokyo Medical and Dental University, Tokyo, Japan.
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