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Healthy Human Tissues Often Express Retrovirus Sequences, Study Finds

NEW YORK – New research suggests that normal, disease-free human tissues may express human endogenous retrovirus (HERV) transcripts stemming from ancient viruses in the provirus group HERV-K, also known as HML-2 viruses.

"While the activity of recently integrated HML-2 proviruses has been previously studied in a number of disease contexts, their activity in non-diseased tissue has been largely unexplored," senior and corresponding author John Coffin, a researcher at Tufts University, and his colleagues wrote in PLOS Biology, adding that the current HML-2 expression analysis is expected to "serve as a useful resource for the clinical application of HML-2 moving forward."

The team turned to a multimapping read alignment program called Telescope to search for sequences from specific HML-2 viruses in RNA sequence data for some 13,000 samples spanning 54 tissue types in nearly 950 individuals profiled for the National Institute of Health's Genotype-Tissue Expression (GTEx) project, uncovering HML-2 expression in a wide range of apparently normal, healthy tissue samples and types.

The researchers noted that 37 distinct proviruses turned up in at least one of the tissues profiled, often in a tissue-specific fashion. The expression of viruses from the HML-2 group was particularly pronounced in specific tissues, including the brain's cerebellum region, pituitary or thyroid tissues, and the testis.

"We have found that nearly all normal human tissues express, in their RNA, one or another of about three dozen endogenous proviruses, remnants of widespread retrovirus infection of our distant ancestors," Coffin said in a statement. "We expect this finding to provide a basis for further studies to understand the role of these elements in human biology and disease."

In particular, the authors explained, their results suggested that "the oldest proviruses are the most expressed and most frequent provirus expression was seen in neuronal, endocrine, and reproductive tissue."

Along with variable HML-2 virus expression from one tissue to the next, the researchers saw signs that representation of the viruses varies between individuals and, to some extent, with age and between male and female participants.

"Similar to the effects of biological sex, the age of the donors appears to affect specific proviruses in individual body sites," the authors reported, noting that a provirus found at a specific site on chromosome 3 showed particularly pronounced age-related expression shifts in more than one of the tissue types considered.

Even so, the investigators emphasized that findings from past research points to higher-than-usual expression of some HML-2 virus sequences in a subset of human cancer types, highlighting the importance of further analyses that delve into typical HERV distribution, expression profiles, and identities across specific tissue types and sites in the genome.

"Our findings suggest that more work will be required to understand HML-2 transcription in disease states," the authors noted, explaining that "significant differences in expression among individual proviruses in healthy tissue demonstrate that the measurement of a total family or subtype of HERVs obscures much of the biology taking place with respect to individual proviruses."

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