Reconstitution of an infectious human endogenous retrovirus

The human genome represents a fossil record of ancient retroviruses that once replicated in the ancestors of contemporary humans. Indeed, approximately 8% of human DNA is composed of sequences that are recognizably retroviral. Despite occasional reports associating human endogenous retrovirus (HERV)...

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Bibliographic Details
Published in:PLoS pathogens 2007-01, Vol.3 (1), p.e10-e10
Main Authors: Lee, Young Nam, Bieniasz, Paul D
Format: Article
Language:English
Subjects:
Analysis
Apolipoproteins
Cloning
Cytomegalovirus
Endogenous Retroviruses - genetics
Endogenous Retroviruses - physiology
Evolution, Molecular
Experiments
Genes
Genome, Viral
Genomes
Human endogenous retrovirus
Human genome
Human immunodeficiency virus 1
Humans
Monkeys & apes
Mutation
Open Reading Frames
Polypeptides
Proviruses - genetics
Retroviruses
Transduction, Genetic
Tropism
Virion - genetics
Virology
Virus Assembly
Virus Integration
Virus Replication
Viruses
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Summary:The human genome represents a fossil record of ancient retroviruses that once replicated in the ancestors of contemporary humans. Indeed, approximately 8% of human DNA is composed of sequences that are recognizably retroviral. Despite occasional reports associating human endogenous retrovirus (HERV) expression with human disease, almost all HERV genomes contain obviously inactivating mutations, and none are thought to be capable of replication. Nonetheless, one family of HERVs, namely HERV-K(HML-2), may have replicated in human ancestors less than 1 million years ago. By deriving a consensus sequence, we reconstructed a proviral clone (HERV-KCON) that likely resembles the progenitor of HERV-K(HML-2) variants that entered the human genome within the last few million years. We show that HERV-KCON Gag and protease proteins mediate efficient assembly and processing into retrovirus-like particles. Moreover, reporter genes inserted into the HERV-KCON genome and packaged into HERV-K particles are capable of infectious transfer and stable integration in a manner that requires reverse transcription. Additionally, we show that HERV-KCON Env is capable of pseudotyping HIV-1 particles and mediating entry into human and nonhuman cell lines. Furthermore, we show that HERV-KCON is resistant to inhibition by the human retrovirus restriction factors tripartite motif 5alpha and apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) 3G but is inhibited by APOBEC 3F. Overall, the resurrection of this extinct infectious agent in a functional form from molecular fossils should enable studies of the molecular virology and pathogenic potential of this ancient human retrovirus.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.0030010