APOBEC3C Tandem Domain Proteins Create Super Restriction Factors against HIV-1

ABSTRACT Humans encode proteins, called restriction factors, that inhibit replication of viruses such as HIV-1. The members of one family of antiviral proteins, apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3; shortened here to A3), act by deaminating cytidines to uridines...

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Autores principales:	Mollie M. McDonnell, Kate H. D. Crawford, Adam S. Dingens, Jesse D. Bloom, Michael Emerman
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	APOBEC3C HIV-1 restriction factor Vif innate immunity Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/f1374489112c4b6484f89a474867ce79
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spelling	oai:doaj.org-article:f1374489112c4b6484f89a474867ce792021-11-15T15:57:03ZAPOBEC3C Tandem Domain Proteins Create Super Restriction Factors against HIV-110.1128/mBio.00737-202150-7511https://doaj.org/article/f1374489112c4b6484f89a474867ce792020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00737-20https://doaj.org/toc/2150-7511ABSTRACT Humans encode proteins, called restriction factors, that inhibit replication of viruses such as HIV-1. The members of one family of antiviral proteins, apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3; shortened here to A3), act by deaminating cytidines to uridines during the reverse transcription reaction of HIV-1. The A3 locus encodes seven genes, named A3A to A3H. These genes have either one or two cytidine deaminase domains, and several of these A3s potently restrict HIV-1. A3C, which has only a single cytidine deaminase domain, however, inhibits HIV-1 only very weakly. We tested novel double domain protein combinations by genetically linking two A3C genes to make a synthetic tandem domain protein. This protein created a “super restriction factor” that had more potent antiviral activity than the native A3C protein, which correlated with increased packaging into virions. Furthermore, disabling one of the active sites of the synthetic tandem domain protein resulted in an even greater increase in the antiviral activity—recapitulating a similar evolution seen in A3F and A3G (double domain A3s that use only a single catalytically active deaminase domain). These A3C tandem domain proteins do not have an increase in mutational activity but instead inhibit formation of reverse transcription products, which correlates with their ability to form large higher-order complexes in cells. Finally, the A3C-A3C super restriction factor largely escaped antagonism by the HIV-1 viral protein Vif. IMPORTANCE As a part of the innate immune system, humans encode proteins that inhibit viruses such as HIV-1. These broadly acting antiviral proteins do not protect humans from viral infections because viruses encode proteins that antagonize the host antiviral proteins to evade the innate immune system. One such example of a host antiviral protein is APOBEC3C (A3C), which weakly inhibits HIV-1. Here, we show that we can improve the antiviral activity of A3C by duplicating the DNA sequence to create a synthetic tandem domain and, furthermore, that the proteins thus generated are relatively resistant to the viral antagonist Vif. Together, these data give insights about how nature has evolved a defense against viral pathogens such as HIV.Mollie M. McDonnellKate H. D. CrawfordAdam S. DingensJesse D. BloomMichael EmermanAmerican Society for MicrobiologyarticleAPOBEC3CHIV-1restriction factorVifinnate immunityMicrobiologyQR1-502ENmBio, Vol 11, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	APOBEC3C HIV-1 restriction factor Vif innate immunity Microbiology QR1-502
spellingShingle	APOBEC3C HIV-1 restriction factor Vif innate immunity Microbiology QR1-502 Mollie M. McDonnell Kate H. D. Crawford Adam S. Dingens Jesse D. Bloom Michael Emerman APOBEC3C Tandem Domain Proteins Create Super Restriction Factors against HIV-1
description	ABSTRACT Humans encode proteins, called restriction factors, that inhibit replication of viruses such as HIV-1. The members of one family of antiviral proteins, apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3; shortened here to A3), act by deaminating cytidines to uridines during the reverse transcription reaction of HIV-1. The A3 locus encodes seven genes, named A3A to A3H. These genes have either one or two cytidine deaminase domains, and several of these A3s potently restrict HIV-1. A3C, which has only a single cytidine deaminase domain, however, inhibits HIV-1 only very weakly. We tested novel double domain protein combinations by genetically linking two A3C genes to make a synthetic tandem domain protein. This protein created a “super restriction factor” that had more potent antiviral activity than the native A3C protein, which correlated with increased packaging into virions. Furthermore, disabling one of the active sites of the synthetic tandem domain protein resulted in an even greater increase in the antiviral activity—recapitulating a similar evolution seen in A3F and A3G (double domain A3s that use only a single catalytically active deaminase domain). These A3C tandem domain proteins do not have an increase in mutational activity but instead inhibit formation of reverse transcription products, which correlates with their ability to form large higher-order complexes in cells. Finally, the A3C-A3C super restriction factor largely escaped antagonism by the HIV-1 viral protein Vif. IMPORTANCE As a part of the innate immune system, humans encode proteins that inhibit viruses such as HIV-1. These broadly acting antiviral proteins do not protect humans from viral infections because viruses encode proteins that antagonize the host antiviral proteins to evade the innate immune system. One such example of a host antiviral protein is APOBEC3C (A3C), which weakly inhibits HIV-1. Here, we show that we can improve the antiviral activity of A3C by duplicating the DNA sequence to create a synthetic tandem domain and, furthermore, that the proteins thus generated are relatively resistant to the viral antagonist Vif. Together, these data give insights about how nature has evolved a defense against viral pathogens such as HIV.
format	article
author	Mollie M. McDonnell Kate H. D. Crawford Adam S. Dingens Jesse D. Bloom Michael Emerman
author_facet	Mollie M. McDonnell Kate H. D. Crawford Adam S. Dingens Jesse D. Bloom Michael Emerman
author_sort	Mollie M. McDonnell
title	APOBEC3C Tandem Domain Proteins Create Super Restriction Factors against HIV-1
title_short	APOBEC3C Tandem Domain Proteins Create Super Restriction Factors against HIV-1
title_full	APOBEC3C Tandem Domain Proteins Create Super Restriction Factors against HIV-1
title_fullStr	APOBEC3C Tandem Domain Proteins Create Super Restriction Factors against HIV-1
title_full_unstemmed	APOBEC3C Tandem Domain Proteins Create Super Restriction Factors against HIV-1
title_sort	apobec3c tandem domain proteins create super restriction factors against hiv-1
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/f1374489112c4b6484f89a474867ce79
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APOBEC3C Tandem Domain Proteins Create Super Restriction Factors against HIV-1

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