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Highly-potent, synthetic APOBEC3s restrict HIV-1 through deamination-independent mechanisms
- Source :
- PLoS Pathogens, PLoS Pathogens, Vol 17, Iss 6, p e1009523 (2021)
- Publication Year :
- 2021
-
Abstract
- 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.<br />Author summary Antiviral genes are encoded by all organisms to help protect them from viral infections, including proteins encoded by primates to protect them from viruses similar to HIV-1. These antiviral proteins are also called “restriction factors”. Some restriction factors are broadly acting, while others are very specific. During the course of evolution, some of these genes have expanded into multiple copies and rearranged in different versions to give them new activities. In this paper, we validated the hypothesis that one particular antiviral gene family, called the APOBEC3 family, has the capability of making novel combinations of antiviral human genes with as great, or greater, potency against HIV-1 as the most potent natural member of this family. By combining parts of the APOBEC3 proteins into novel combinations, we created potent antiviral versions that act through a mechanism distinct from existing APOBEC3 proteins.
- Subjects :
- RNA viruses
T-Lymphocytes
Gene Expression
HIV Infections
Pathology and Laboratory Medicine
Biochemistry
Virions
Jurkat Cells
White Blood Cells
Immunodeficiency Viruses
Animal Cells
Gene duplication
Medicine and Health Sciences
APOBEC Deaminases
Biology (General)
Mammals
0303 health sciences
Chemistry
T Cells
030302 biochemistry & molecular biology
Eukaryota
Transfection
Cytidine deaminase
3. Good health
Cell biology
medicine.anatomical_structure
Deamination
Medical Microbiology
Viral Pathogens
Viruses
Vertebrates
Pathogens
Cellular Types
Research Article
Primates
QH301-705.5
T cell
Immune Cells
Immunology
Locus (genetics)
Computational biology
Biology
Viral Structure
Research and Analysis Methods
Microbiology
03 medical and health sciences
Protein Domains
Virology
Retroviruses
medicine
Genetics
Humans
Animals
Molecular Biology Techniques
Gene
Microbial Pathogens
Molecular Biology
030304 developmental biology
Blood Cells
Mechanism (biology)
Point mutation
Lentivirus
Organisms
RNA
Biology and Life Sciences
HIV
Proteins
Cell Biology
Reverse Transcription
RC581-607
Reverse transcriptase
Viral Replication
Amniotes
HIV-1
Parasitology
Immunologic diseases. Allergy
Zoology
Subjects
Details
- ISSN :
- 15537374
- Volume :
- 17
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- PLoS pathogens
- Accession number :
- edsair.doi.dedup.....21c704c2fbca65cb3150243eb9d83488