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Mutations in hepatitis C virus p7 reduce both the egress and infectivity of assembled particles via impaired proton channel function

Mutations in hepatitis C virus p7 reduce both the egress and infectivity of assembled particles via impaired proton channel function
Mutations in hepatitis C virus p7 reduce both the egress and infectivity of assembled particles via impaired proton channel function
Hepatitis C virus (HCV) p7 protein is critical for the efficient production of infectious virions in culture. p7 undergoes genotype-specific protein–protein interactions as well as displaying channel-forming activity, making it unclear whether the phenotypes of deleterious p7 mutations result from the disruption of one or both of these functions. Here, we showed that proton channel activity alone, provided in trans by either influenza virus M2 or genotype 1b HCV p7, was both necessary and sufficient to restore infectious particle production to genotype 2a HCV (JFH-1 isolate) carrying deleterious p7 alanine substitutions within the p7 dibasic loop (R33A, R35A), and the N-terminal trans-membrane region (N15?:?C16?:?H17/AAA). Both mutations markedly reduced mature p7 abundance, with those in the dibasic loop also significantly reducing levels of mature E2 and NS2. Interestingly, whilst M2 and genotype 1b p7 restored the same level of intracellular infectivity as JFH-1 p7, supplementing with the isogenic protein led to a further increase in secreted infectivity, suggesting a late-acting role for genotype-specific p7 protein interactions. Finally, cells infected by viruses carrying p7 mutations contained non-infectious core-containing particles with densities equivalent to WT HCV, indicating a requirement for p7 proton channel activity in conferring an infectious phenotype to virions.
0022-1317
2236-2248
Bentham, Matthew
f16580eb-da39-48ad-8fe7-2f290294907c
Foster, Toshana
61295601-0d3b-4773-bade-9d0dda1ebb1f
Christopher, McCormick
0fce14bf-2f67-4d08-991f-114dd1e7f0bd
Griffin, Stephen
49c409b7-ee50-4809-b6b8-d5e192ff7424
Bentham, Matthew
f16580eb-da39-48ad-8fe7-2f290294907c
Foster, Toshana
61295601-0d3b-4773-bade-9d0dda1ebb1f
Christopher, McCormick
0fce14bf-2f67-4d08-991f-114dd1e7f0bd
Griffin, Stephen
49c409b7-ee50-4809-b6b8-d5e192ff7424

Bentham, Matthew, Foster, Toshana, Christopher, McCormick and Griffin, Stephen (2013) Mutations in hepatitis C virus p7 reduce both the egress and infectivity of assembled particles via impaired proton channel function. Journal of General Virology, 94 (10), 2236-2248. (doi:10.1099/vir.0.054338-0). (PMID:23907396)

Record type: Article

Abstract

Hepatitis C virus (HCV) p7 protein is critical for the efficient production of infectious virions in culture. p7 undergoes genotype-specific protein–protein interactions as well as displaying channel-forming activity, making it unclear whether the phenotypes of deleterious p7 mutations result from the disruption of one or both of these functions. Here, we showed that proton channel activity alone, provided in trans by either influenza virus M2 or genotype 1b HCV p7, was both necessary and sufficient to restore infectious particle production to genotype 2a HCV (JFH-1 isolate) carrying deleterious p7 alanine substitutions within the p7 dibasic loop (R33A, R35A), and the N-terminal trans-membrane region (N15?:?C16?:?H17/AAA). Both mutations markedly reduced mature p7 abundance, with those in the dibasic loop also significantly reducing levels of mature E2 and NS2. Interestingly, whilst M2 and genotype 1b p7 restored the same level of intracellular infectivity as JFH-1 p7, supplementing with the isogenic protein led to a further increase in secreted infectivity, suggesting a late-acting role for genotype-specific p7 protein interactions. Finally, cells infected by viruses carrying p7 mutations contained non-infectious core-containing particles with densities equivalent to WT HCV, indicating a requirement for p7 proton channel activity in conferring an infectious phenotype to virions.

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More information

e-pub ahead of print date: 1 August 2013
Published date: October 2013
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 361183
URI: https://eprints.soton.ac.uk/id/eprint/361183
ISSN: 0022-1317
PURE UUID: b79b1e32-ef3f-4fb6-9193-596af3514f51
ORCID for McCormick Christopher: ORCID iD orcid.org/0000-0002-6155-9161

Catalogue record

Date deposited: 15 Jan 2014 12:48
Last modified: 20 Jul 2019 00:55

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