Highly-potent, synthetic APOBEC3s restrict HIV-1 through deamination-independent mechanisms.

The APOBEC3 (A3) genes encode cytidine deaminase proteins with potent antiviral and anti-retroelement activity. This locus is characterized by duplication, recombination, and deletion events that gave rise to the seven A3s found in primates. These include three single deaminase domain A3s (A3A, A3C,...

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Autores principales:	Mollie M McDonnell, Suzanne C Karvonen, Amit Gaba, Ben Flath, Linda Chelico, Michael Emerman
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/f3ee784f8bc14f40a6c8aa3e3234e59c
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spelling	oai:doaj.org-article:f3ee784f8bc14f40a6c8aa3e3234e59c2021-12-02T20:00:17ZHighly-potent, synthetic APOBEC3s restrict HIV-1 through deamination-independent mechanisms.1553-73661553-737410.1371/journal.ppat.1009523https://doaj.org/article/f3ee784f8bc14f40a6c8aa3e3234e59c2021-06-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1009523https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374The APOBEC3 (A3) genes encode cytidine deaminase proteins with potent antiviral and anti-retroelement activity. This locus is characterized by duplication, recombination, and deletion events that gave rise to the seven A3s found in primates. These include three single deaminase domain A3s (A3A, A3C, and A3H) and four double deaminase domain A3s (A3B, A3D, A3F, and A3G). The most potent of the A3 proteins against HIV-1 is A3G. However, it is not clear if double deaminase domain A3s have a generalized functional advantage to restrict HIV-1. In order to test whether superior restriction factors could be created by genetically linking single A3 domains into synthetic double domains, we linked A3C and A3H single domains in novel combinations. We found that A3C/A3H double domains acquired enhanced antiviral activity that is at least as potent, if not better than, A3G. Although these synthetic double domain A3s package into budding virions more efficiently than their respective single domains, this does not fully explain their gain of antiviral potency. The antiviral activity is conferred both by cytidine-deaminase dependent and independent mechanisms, with the latter correlating to an increase in RNA binding affinity. T cell lines expressing this A3C-A3H super restriction factor are able to control replicating HIV-1ΔVif infection to similar levels as A3G. Together, these data show that novel combinations of A3 domains are capable of gaining potent antiviral activity to levels similar to the most potent genome-encoded A3s, via a primarily non-catalytic mechanism.Mollie M McDonnellSuzanne C KarvonenAmit GabaBen FlathLinda ChelicoMichael EmermanPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 6, p e1009523 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Mollie M McDonnell Suzanne C Karvonen Amit Gaba Ben Flath Linda Chelico Michael Emerman Highly-potent, synthetic APOBEC3s restrict HIV-1 through deamination-independent mechanisms.
description	The APOBEC3 (A3) genes encode cytidine deaminase proteins with potent antiviral and anti-retroelement activity. This locus is characterized by duplication, recombination, and deletion events that gave rise to the seven A3s found in primates. These include three single deaminase domain A3s (A3A, A3C, and A3H) and four double deaminase domain A3s (A3B, A3D, A3F, and A3G). The most potent of the A3 proteins against HIV-1 is A3G. However, it is not clear if double deaminase domain A3s have a generalized functional advantage to restrict HIV-1. In order to test whether superior restriction factors could be created by genetically linking single A3 domains into synthetic double domains, we linked A3C and A3H single domains in novel combinations. We found that A3C/A3H double domains acquired enhanced antiviral activity that is at least as potent, if not better than, A3G. Although these synthetic double domain A3s package into budding virions more efficiently than their respective single domains, this does not fully explain their gain of antiviral potency. The antiviral activity is conferred both by cytidine-deaminase dependent and independent mechanisms, with the latter correlating to an increase in RNA binding affinity. T cell lines expressing this A3C-A3H super restriction factor are able to control replicating HIV-1ΔVif infection to similar levels as A3G. Together, these data show that novel combinations of A3 domains are capable of gaining potent antiviral activity to levels similar to the most potent genome-encoded A3s, via a primarily non-catalytic mechanism.
format	article
author	Mollie M McDonnell Suzanne C Karvonen Amit Gaba Ben Flath Linda Chelico Michael Emerman
author_facet	Mollie M McDonnell Suzanne C Karvonen Amit Gaba Ben Flath Linda Chelico Michael Emerman
author_sort	Mollie M McDonnell
title	Highly-potent, synthetic APOBEC3s restrict HIV-1 through deamination-independent mechanisms.
title_short	Highly-potent, synthetic APOBEC3s restrict HIV-1 through deamination-independent mechanisms.
title_full	Highly-potent, synthetic APOBEC3s restrict HIV-1 through deamination-independent mechanisms.
title_fullStr	Highly-potent, synthetic APOBEC3s restrict HIV-1 through deamination-independent mechanisms.
title_full_unstemmed	Highly-potent, synthetic APOBEC3s restrict HIV-1 through deamination-independent mechanisms.
title_sort	highly-potent, synthetic apobec3s restrict hiv-1 through deamination-independent mechanisms.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/f3ee784f8bc14f40a6c8aa3e3234e59c
work_keys_str_mv	AT molliemmcdonnell highlypotentsyntheticapobec3srestricthiv1throughdeaminationindependentmechanisms AT suzanneckarvonen highlypotentsyntheticapobec3srestricthiv1throughdeaminationindependentmechanisms AT amitgaba highlypotentsyntheticapobec3srestricthiv1throughdeaminationindependentmechanisms AT benflath highlypotentsyntheticapobec3srestricthiv1throughdeaminationindependentmechanisms AT lindachelico highlypotentsyntheticapobec3srestricthiv1throughdeaminationindependentmechanisms AT michaelemerman highlypotentsyntheticapobec3srestricthiv1throughdeaminationindependentmechanisms
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Highly-potent, synthetic APOBEC3s restrict HIV-1 through deamination-independent mechanisms.

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