Retroviruses, retroelements and their restrictions

Retroviruses have a unique evolutionary association with their host; having a fossil record on the genomic DNA of the host chromosome. Most mammalian genomes carry, as part of their genetic make-up, retroviruses in the form of endogenous proviruses that are inherited like cellular genes following germ-line transmission of some retroviral genomes, accumulated throughout evolution in many organisms. Indeed, recently available genomic data revealed that a large portion of the mammalian genome is derived from ancient transposable elements. In particular, retroelements, transported by an intracellular copy-and-paste process involving an RNA intermediate, constitute a majority of these mobile genetic elements. Endogenous retroviruses, also called long-terminal-repeat (LTR)-type retroelements, are structurally similar to infectious retroviruses and constitute one class of these retroelements in a range of mammalian species. The non-LTR members, with reverse transcription occurring exclusively within the nucleus, are present in extremely high copy numbers; with long interspersed nuclear elements (LINEs) contributing close to 40% of human and murine genomes. These LINE elements modify mammalian genomes not only through insertions, but also by indirect replication of nonautonomous retrotransposons such as short interspersed nuclear elements (SINEs) and processed pseudogenes. The ability of both LTR-type and non-LTR-type retroelements to move within host genomes gives these genetic elements an intrinsic propensity to affect genome evolution and speciation. As expected, cellular machineries of vertebrate’s intrinsic immune system have evolved to support a balance between retroelement insertions that confer beneficial genetic diversity and those that cause deleterious gene disruptions. The evolution of retroviruses, retroelements and their hosts appear to be intertwined, and studies of intrinsic immunity have just begun to uncover interesting dimensions in the complex and ongoing battle between retroviruses, retroelements and their hosts. While host adaptive and innate immunity are primarily responsible for providing protection against exogenous microbial pathogens, it is becoming increasingly clear that intrinsic, inhibitory activities can also have an important role in controlling endogenous invaders.

In this Research Topic, our current understanding of the cellular machineries of vertebrate’s intrinsic immunity that function against retrovirus and retroelement is reviewed. One class of such intrinsic inhibitors, AID/APOBEC cytidine deaminases, which regulate the mobility of retrotransposons in a variety of mammalian species, will be highlighted. The molecular biology for the replication cycle of the non-LTR retrotransposon, also called target-primed retrotransposons, will also be described. Characterization of these molecular mechanisms should help to further our understanding and provide critical insights into important issues such as zoonotic (cross-species) transmission of exogenous microbial pathogens. Additionally, elucidation of intracellular repressive activities may lead to the clinical benefits, such as the development of novel therapeutic interventions against infectious retroviruses.