Abstract
Human endogenous retrovirus (HERV-K (HML-2)) proviruses are among the few endogenous retroviral elements in the human genome that retain coding sequence. HML-2 expression has been widely associated with human disease states, including different types of cancers as well as with HIV-1 infection. Understanding of the potential impact of this expression requires that it be annotated at the proviral level. Here, we utilized the high throughput capabilities of next-generation sequencing to profile HML-2 expression at the level of individual proviruses and secreted virions in the teratocarcinoma cell line Tera-1. We identified well-defined expression patterns, with transcripts emanating primarily from two proviruses located on chromosome 22, only one of which was efficiently packaged. Interestingly, there was a preference for transcripts of recently integrated proviruses, over those from other highly expressed but older elements, to be packaged into virions. We also assessed the promoter competence of the 5’ long terminal repeats (LTRs) of expressed proviruses via a luciferase assay following transfection of Tera-1 cells. Consistent with the RNASeq results, we found that the activity of most LTRs corresponded to their transcript levels.
Highlights
The genomes of all mammals, and of most or all vertebrates, contain sequences of retroviral origin
HML-2 RNA originating from the provirus at chromosome 22q11.21 and other evolutionarily young integrations [13], and its virions appear to be immature and lacking Env glycoprotein [12]
A predicted complication in applying this approach to HML-2 transcription profiling is caused by the high sequence similarity between recently integrated HML-2 proviruses (Figure 1B)
Summary
The genomes of all mammals, and of most or all vertebrates, contain sequences of retroviral origin. Retroviruses have the unique ability to convert their ssRNA genome into dsDNA, which is irreversibly integrated, as a provirus, into the host genome as part of the replication cycle. Though infection generally occurs through horizontal transfer, where a retrovirus infects a somatic cell, replicates and is passed from cell to cell and from one individual to another, proviruses resulting from infection of germline cells can be inherited and transferred vertically, from parent to offspring [1]. Human endogenous retroviruses (HERVs) are the vestiges of infection of the germline cells of our ancestors and comprise ~8% of the genome [2]. Once integrated into the genome, HERVs are inherited in a Mendelian fashion, akin to genes, and subject to similar selection pressures, as insertions can have beneficial, detrimental or neutral effects on a host [3].
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