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Host Genetic Variants in the Pathogenesis of Hepatitis C
Viruses 2012, 4(12), 3303-3315; doi:10.3390/v4123303
Article

Subtype Specific Differences in NS5A Domain II Reveals Involvement of Proline at Position 310 in Cyclosporine Susceptibility of Hepatitis C Virus

1
 and 1,2,*
Received: 11 October 2012; in revised form: 17 November 2012 / Accepted: 20 November 2012 / Published: 22 November 2012
(This article belongs to the Special Issue Cyclophilins and Viruses)
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Abstract: Hepatitis C virus (HCV) is susceptible to cyclosporine (CsA) and other cyclophilin (CypA) inhibitors, but the genetic basis of susceptibility is controversial. Whether genetic variation in NS5A alters cell culture susceptibility of HCV to CypA inhibition is unclear. We constructed replicons containing NS5A chimeras from genotypes 1a, 2a and 4a to test how variation in carboxy terminal regions of NS5A altered the genotype 1b CsA susceptibility. All chimeric replicons including genotype 1b Con1LN-wt replicon exhibited some cell culture sensitivity to CsA with genotype 4a being most sensitive and 1a the least. The CypA binding pattern of truncated NS5A genotypes correlated with the susceptibility of these replicons to CsA. The Con1LN-wt replicon showed increased susceptibility towards CsA when proline at position 310P was mutated to either threonine or alanine. Furthermore, a 15 amino acid long peptide fused N terminally to GFP coding sequences confirmed involvement of proline at 310 in CypA binding. Our findings are consistent with CypA acting on multiple prolines outside of the previously identified CypA binding sites. These results suggest multiple specific genetic variants between genotype 1a and 1b in the C-terminus of NS5A alter the CsA susceptibility of replicons, and some variants may oppose the effects of others.
Keywords: Hepatitis C virus; cyclosporine; cyclophilin; susceptibility Hepatitis C virus; cyclosporine; cyclophilin; susceptibility
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Ansari, I.-U.H.; Striker, R. Subtype Specific Differences in NS5A Domain II Reveals Involvement of Proline at Position 310 in Cyclosporine Susceptibility of Hepatitis C Virus. Viruses 2012, 4, 3303-3315.

AMA Style

Ansari I-UH, Striker R. Subtype Specific Differences in NS5A Domain II Reveals Involvement of Proline at Position 310 in Cyclosporine Susceptibility of Hepatitis C Virus. Viruses. 2012; 4(12):3303-3315.

Chicago/Turabian Style

Ansari, Israr-ul H.; Striker, Rob. 2012. "Subtype Specific Differences in NS5A Domain II Reveals Involvement of Proline at Position 310 in Cyclosporine Susceptibility of Hepatitis C Virus." Viruses 4, no. 12: 3303-3315.


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