Nonstructural Proteins Are Preferential Positive Selection Targets in Zika Virus and Related Flaviviruses.
The Flavivirus genus comprises several human pathogens such as dengue virus (DENV), Japanese encephalitis virus (JEV), and Zika virus (ZIKV). Although ZIKV usually causes mild symptoms, growing evidence is linking it to congenital birth defects and to increased risk of Guillain-Barré syndrome. ZIKV...
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ftdoajarticles:oai:doaj.org/article:c14ec14587b247719aadb9d5234220ae 2023-05-15T15:15:55+02:00 Nonstructural Proteins Are Preferential Positive Selection Targets in Zika Virus and Related Flaviviruses. Manuela Sironi Diego Forni Mario Clerici Rachele Cagliani 2016-09-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0004978 https://doaj.org/article/c14ec14587b247719aadb9d5234220ae EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC5010288?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0004978 https://doaj.org/article/c14ec14587b247719aadb9d5234220ae PLoS Neglected Tropical Diseases, Vol 10, Iss 9, p e0004978 (2016) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2016 ftdoajarticles https://doi.org/10.1371/journal.pntd.0004978 2022-12-31T14:58:52Z The Flavivirus genus comprises several human pathogens such as dengue virus (DENV), Japanese encephalitis virus (JEV), and Zika virus (ZIKV). Although ZIKV usually causes mild symptoms, growing evidence is linking it to congenital birth defects and to increased risk of Guillain-Barré syndrome. ZIKV encodes a polyprotein that is processed to produce three structural and seven nonstructural (NS) proteins. We investigated the evolution of the viral polyprotein in ZIKV and in related flaviviruses (DENV, Spondweni virus, and Kedougou virus). After accounting for saturation issues, alignment uncertainties, and recombination, we found evidence of episodic positive selection on the branch that separates DENV from the other flaviviruses. NS1 emerged as the major selection target, and selected sites were located in immune epitopes or in functionally important protein regions. Three of these sites are located in an NS1 region that interacts with structural proteins and is essential for virion biogenesis. Analysis of the more recent evolutionary history of ZIKV lineages indicated that positive selection acted on NS5 and NS4B, this latter representing the preferential target. All selected sites were located in the N-terminal portion of NS4B, which inhibits interferon response. One of the positively selected sites (26M/I/T/V) in ZIKV also represents a selection target in sylvatic DENV2 isolates, and a nearby residue evolves adaptively in JEV. Two additional positively selected sites are within a protein region that interacts with host (e.g. STING) and viral (i.e. NS1, NS4A) proteins. Notably, mutations in the NS4B region of other flaviviruses modulate neurovirulence and/or neuroinvasiveness. These results suggest that the positively selected sites we identified modulate viral replication and contribute to immune evasion. These sites should be prioritized in future experimental studies. However, analyses herein detected no selective events associated to the spread of the Asian/American ZIKV lineage. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic Barré ENVELOPE(-68.550,-68.550,-67.500,-67.500) PLOS Neglected Tropical Diseases 10 9 e0004978 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Manuela Sironi Diego Forni Mario Clerici Rachele Cagliani Nonstructural Proteins Are Preferential Positive Selection Targets in Zika Virus and Related Flaviviruses. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
The Flavivirus genus comprises several human pathogens such as dengue virus (DENV), Japanese encephalitis virus (JEV), and Zika virus (ZIKV). Although ZIKV usually causes mild symptoms, growing evidence is linking it to congenital birth defects and to increased risk of Guillain-Barré syndrome. ZIKV encodes a polyprotein that is processed to produce three structural and seven nonstructural (NS) proteins. We investigated the evolution of the viral polyprotein in ZIKV and in related flaviviruses (DENV, Spondweni virus, and Kedougou virus). After accounting for saturation issues, alignment uncertainties, and recombination, we found evidence of episodic positive selection on the branch that separates DENV from the other flaviviruses. NS1 emerged as the major selection target, and selected sites were located in immune epitopes or in functionally important protein regions. Three of these sites are located in an NS1 region that interacts with structural proteins and is essential for virion biogenesis. Analysis of the more recent evolutionary history of ZIKV lineages indicated that positive selection acted on NS5 and NS4B, this latter representing the preferential target. All selected sites were located in the N-terminal portion of NS4B, which inhibits interferon response. One of the positively selected sites (26M/I/T/V) in ZIKV also represents a selection target in sylvatic DENV2 isolates, and a nearby residue evolves adaptively in JEV. Two additional positively selected sites are within a protein region that interacts with host (e.g. STING) and viral (i.e. NS1, NS4A) proteins. Notably, mutations in the NS4B region of other flaviviruses modulate neurovirulence and/or neuroinvasiveness. These results suggest that the positively selected sites we identified modulate viral replication and contribute to immune evasion. These sites should be prioritized in future experimental studies. However, analyses herein detected no selective events associated to the spread of the Asian/American ZIKV lineage. |
format |
Article in Journal/Newspaper |
author |
Manuela Sironi Diego Forni Mario Clerici Rachele Cagliani |
author_facet |
Manuela Sironi Diego Forni Mario Clerici Rachele Cagliani |
author_sort |
Manuela Sironi |
title |
Nonstructural Proteins Are Preferential Positive Selection Targets in Zika Virus and Related Flaviviruses. |
title_short |
Nonstructural Proteins Are Preferential Positive Selection Targets in Zika Virus and Related Flaviviruses. |
title_full |
Nonstructural Proteins Are Preferential Positive Selection Targets in Zika Virus and Related Flaviviruses. |
title_fullStr |
Nonstructural Proteins Are Preferential Positive Selection Targets in Zika Virus and Related Flaviviruses. |
title_full_unstemmed |
Nonstructural Proteins Are Preferential Positive Selection Targets in Zika Virus and Related Flaviviruses. |
title_sort |
nonstructural proteins are preferential positive selection targets in zika virus and related flaviviruses. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2016 |
url |
https://doi.org/10.1371/journal.pntd.0004978 https://doaj.org/article/c14ec14587b247719aadb9d5234220ae |
long_lat |
ENVELOPE(-68.550,-68.550,-67.500,-67.500) |
geographic |
Arctic Barré |
geographic_facet |
Arctic Barré |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 10, Iss 9, p e0004978 (2016) |
op_relation |
http://europepmc.org/articles/PMC5010288?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0004978 https://doaj.org/article/c14ec14587b247719aadb9d5234220ae |
op_doi |
https://doi.org/10.1371/journal.pntd.0004978 |
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PLOS Neglected Tropical Diseases |
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10 |
container_issue |
9 |
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e0004978 |
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