INVESTIGADORES
LAUFER Natalia Lorna
artículos
Título:
Analysis of sequences of hepatitis C virus NS5A genotype 1 in HIV-coinfected patients with a null response to nitazoxanide or peg-interferon plus ribavirin
Autor/es:
MARIANO SEDE; NATALIA LAUFER; DIEGO OJEDA; ANA GUN; PEDRO CAHN; JORGE QUALERI
Revista:
ARCHIVES OF VIROLOGY
Editorial:
SPRINGER WIEN
Referencias:
Lugar: Viena; Año: 2013 vol. 158 p. 1907 - 1915
ISSN:
0304-8608
Resumen:
Even though new drugs have been approved for
treatment of hepatitis C virus (HCV) infection, the risk of
drug-drug interactions and concern about overlapping toxicities
has hindered the development of studies in HIV/HCVcoinfected
individuals. Traditional treatment with pegylated
interferon plus ribavirin (peg-IFN ? RBV) is very expensive
and has a low rate of sustained virological response in
coinfected patients, especially if they are infected with HCV
genotype 1. Nitazoxanide (NTZ) is a drug that is being
evaluated for the treatment of chronic HCV infection, both in
HCV-monoinfected and HIV/HCV-coinfected patients.
Understanding the NTZ resistance mechanism could allow
the development of resistance to be minimized and would
expand the treatment options, mainly in special populations
such as HIV/HCV-coinfected patients. Similarly to IFN,
NTZ increases the activity of the cellular protein kinase
activated by double-stranded RNA (PKR), a key kinase in the
innate antiviral response. In order to elucidate whether
sequence heterogeneity in the PKR-binding domain of HCV
NS5A genotype 1 could influence the antiviral activity of
either NTZ monotherapy or peg-IFN ? RBV, baseline and
end-of-therapy plasma samples from two groups of eleven
non-responder HIV/HCV-coinfected patients that had
received NTZ or peg-IFN ? RBV were studied. Most of the
HCV NS5A sequences examined at the end of therapy did
not change from the baseline, even after 30 days course of
antiviral therapy. An extensive comparison of HCV NS5A
genotype 1 and 4 sequences from the database with reported
IFN therapy outcome was performed in order to infer their
phylogenetic relationships. The HCV genotype 1 NS5A
nucleotide sequences from therapy-non-responder patients
were intermingled amongst those from the database, irrespective
of their IFN-therapy outcome. When comparing
NS5A-PKRBD amino acid sequences, significant differences
were observed in genotype 4, but not in genotype 1
(p\0.0001 and p[0.05, respectively). In conclusion,
despite IFN and NTZ sharing the protein kinase activated by
double-stranded RNA as their cellular target, the HCV
genotype 1 strategy to counteract the IFN action mediated by
NS5A ISDR/PKRBD does not explain drug resistance in
HIV/HCV-coinfected patients. Other viral factors that are
possibly involved are discussed as well.