Integration of arenavirus DNA into the cell genome

27 January 2009

retrotransposonIs that title correct? Arenaviruses have an RNA genome which is not known to be copied into DNA at any stage of the replication cycle. How could a DNA copy of this virus be produced and be inserted into the host genome?

The RNA genome of retroviruses is converted to a DNA form during viral replication by the viral enzyme reverse transcriptase. The viral DNA then integrates into the host’s genome, becoming a permanent part of the cell. These events have no counterparts during replication of arenaviruses. The RNA genomes of these viruses are copied via an RNA intermediate, entirely in the cytoplasm of the cell. Nevertheless, the authors of a recent study found a DNA copy of the RNA genome of lymphocytic choriomeningitis virus (LCMV), a commonly studied arenavirus, integrated into host cell DNA.

This unusual story began in 1979 with the report that DNA complementary to the RNA genome of LCMV can be detected in about 1 in 103 to 104 infected cells. The authors speculated that retroviruses were involved but did not provide mechanistic evidence. Eighteen years later, the authors subcloned these cells to produce cell lines containing LCMV DNA. They then used polymerase chain reaction to isolate LCMV DNA from the cloned cells, including the cellular sequence flanking the viral genome. Nucleotide sequence analysis revealed that both cell lines contain a copy of the viral glycoprotein (GP) gene joined to cellular sequences encoding an IAP (intracisternal A type) retrotransposon. The authors identified LCMV integration both in cultured cells and infected mice.

Retrotransposons are sequences related to retroviruses that are found in the genome of many organisms. The gene content and arrangement are similar to retroviruses, but they lack an extracellular phase: they do not encode an env gene. Retrotransposons may be retroviral progenitors, or degenerate forms of these viruses. They are amazingly abundant: 42% of the human genome is made up of retrotransposons.

Based on their experimental results, the authors proposed that the following events occurred in a cell infected with LCVM. During copying of the retrotransposon RNA into a cDNA copy by reverse transcriptase, the enzyme switched templates and began copying the LCMV GP RNA. This hybrid DNA – retrotransposon linked to LCVM sequences –  then integrated into the host genome.

The results reported in this paper have enormous implications for evolution and for human gene therapy. Because retrotransposons transpose most efficiently in the thymus and testicles, the recombination events described could lead to transmission of RNA virus genes in the germline. Therefore the contribution of non-retroviral RNA viruses to evolution of the mammalian genome might be greater than previously believed. In addition, it is possible that RNA virus vectors used for gene therapy could integrate into the human genome via the mechanism described in this study. Such integration could lead to undesired mutation such as activation of oncogenes. Therefore the ability of specific RNA virus vectors to integrate into the human genome should be carefully tested before the vectors are approved for use in humans.

Rolf M. Zinkernagel, Paul Klenerman, Hans Hengartner (1997). A non-retroviral RNA virus persists in DNA form Nature, 390 (6657), 298-301 DOI: 10.1038/36876

M. B. Geuking, J. Weber, M. Dewannieux, E. Gorelik, T. Heidmann, H. Hengartner, R. M. Zinkernagel, L. Hangartner (2009). Recombination of Retrotransposon and Exogenous RNA Virus Results in Nonretroviral cDNA Integration Science, 323 (5912), 393-396 DOI: 10.1126/science.1167375

  • Rashid

    Sir,Its very interesting finding that RNA viruses can integrate their virome in to human genome.The retrotranspsons are responsible for integration process.Is there any evidence of dsRNA virome integration in human genome.If we succeed in finding the genomes of RNA viruses,its really as important as HERV archive present in our genome.If they inherit in mendelian fashion,we can give the term V – linked inheritance:Virus Inheritance pattern in Human genome.

    Sir,I guess there might be retrotransposon – independent integration in other dsRNA viruses,but after integration we fail to find out the virus RNA genome,as during host genome replication virus RNA genome will be replaced by the
    DNA from DNA polymerases.Retrotransoson mediated RNA virome integration may not be universal.

  • profvrr

    You are correct, retrotransposon mediated insertion might not be
    universal. The example in this paper was observed after laboratory
    manipulation; there is no evidence for viral genomes, except for
    retroviruses, in mammalian genomes. Clearly more work needs to be done
    to answer these interesting questions.

  • eyalmm

    Hi all,

    More studies have been published about this fascinating phenomena;

    Maori, E., Tanne, E., and Sela, I., Reciprocal sequence exchange between non-retro viruses and hosts leading to the appearance of new host phenotypes. Virology, 2007. 362(2): p. 342-9.

    Tanne, E., and Sela, I., Occurrence of a DNA sequence of a non-retro RNA virus in a host plant genome and its expression: evidence for recombination between viral and host RNAs. Virology, 2005. 332: p. 614-622.

  • eyalmm

    Hi all,

    More studies have been published about this fascinating phenomena;

    Maori, E., Tanne, E., and Sela, I., Reciprocal sequence exchange between non-retro viruses and hosts leading to the appearance of new host phenotypes. Virology, 2007. 362(2): p. 342-9.

    Tanne, E., and Sela, I., Occurrence of a DNA sequence of a non-retro RNA virus in a host plant genome and its expression: evidence for recombination between viral and host RNAs. Virology, 2005. 332: p. 614-622.

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  • brad

    They took a mouse infected with an arenavirus and cured it with IL-7. The media claimed “IL-7 cures HIV mouse!”…….how similar are arenoviruses to HIV? Does this experiment really provide hope that an IL-7-containing regimen could cure HIV in humans?

  • http://www.virology.ws profvrr

    I’m not aware of that study, could you provide a link? However
    arenaviruses and HIV are completely different, and the experiment has
    no bearing on HIV infection.

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