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Cited by 311Chromosomal and Genetic VariationsHIV Research and TreatmentEvolution and Genetic Dynamics

Reconstitution of an Infectious Human Endogenous Retrovirus

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Lee, Young Nam, Bieniasz, Paul D·2007·PLoS Pathogens
DOI 10.1371/journal.ppat.0030010PMC PMC1781480
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Abstract

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.

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  • Reconstruction of a consensus HERV-K (HML2) provirus by assembly and alignment of all complete but defective HERV-K (HML2) proviruses resulted in a replication-competent recombinant retrovirus.

    “Interestingly, reconstruction of a consensus HERV-K (HML2) provirus by assembly and alignment of all of the complete, but defective HERV-K (HML2) proviruses resulted in a replication-competent recombinant retrovirus 84,85.”

    From Are human endogenous retroviruses pathogenic? An approach to testing the hypothesis (2013) · cites this paper as [85]

    The Results section on HERV-KCON design (page unavailable) says the authors derived a consensus from ten selected full-length HERV-K(HML-2) proviruses, not all complete proviruses. The Results section on infectious virions reports single-cycle infectious transfer using a reporter construct with a disrupted env gene and an envelope protein supplied separately. The paper supports reconstruction of an infectious HERV-K–based system, but not the claim that this produced a self-sustaining, replication-competent retrovirus. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • Engineered recombinant HERV-K constructs that contain all open reading frames are capable of viral transmission in cell culture.

    “Engineered recombinant HERV-K constructs that contain all open reading frames are capable of viral transmission in cell culture”

    From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Lee & Bieniasz 2007

    The Results section, “Generation of HERV-KCON–Based Infectious Virions” (page not available), reports infectious transfer in cell culture using engineered HERV-KCON particles. But the infectious construct had a disrupted Env open reading frame and required VSV-G supplied separately. In “HERV-KCON Tropism,” the authors report no detectable infection when they combined HERV-KCON cores with HERV-KCON Env, so the paper does not demonstrate transmission by a construct containing all open reading frames. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Authors
Lee, Y. N., & Bieniasz, P. D.
Affiliations
Aaron Diamond AIDS Research Center (US)
Corresponding author
Bieniasz, Paul D
ORCID
Bieniasz, Paul D
Venue
PLoS Pathogens
Publisher
Public Library of Science (PLoS)
Published
2007-01-26
Volume
3
Issue
1
Pages
e10
ISSN
  • 1553-7366 (ISSN-L)
  • 1553-7374
DOI
10.1371/journal.ppat.0030010
PMC
PMC1781480
OpenAlex
W2059722830
Cited by
311
References
58
Citations by year
2026: 8 · 2025: 5 · 2024: 17 · 2023: 9 · 2022: 15 · 2021: 17 · 2020: 4 · 2019: 15 · 2018: 16 · 2017: 12 · 2016: 23 · 2015: 26 · 2014: 24 · 2013: 27 · 2012: 10
FWCI
29.16
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Pathogens (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • National Institutes of Health
  • National Institute of Allergy and Infectious Diseases (R01 AI64003, R01AI064003)
Topics
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
Keywords
human endogenous retroviruses, HERV-K(HML-2), retrovirus-like particles, reverse transcription, retroviral integration, APOBEC3G, APOBEC3F, TRIM5α, molecular fossils
MeSH terms
Humans, Proviruses, Transduction, Genetic, Virion, Virus Replication, Open Reading Frames, Virus Integration, Genome, Viral, Tropism, Virus Assembly, Evolution, Molecular, Endogenous Retroviruses

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