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Researchers Characterize Virome Response to Therapeutics

NEW YORK (GenomeWeb News) – As organ transplant patients are treated with immunosuppressant and antiviral drugs, their virome undergoes certain changes, as researchers led by Stanford University's Stephen Quake determined through sequencing cell-free DNA from patient plasma and reported in Cell today.

The microbiome, the researchers noted, has been linked to human health and disease, though the virome — the viral component of the microbiome — hasn't been studied in as much depth. By following how the virome of nearly 100 organ transplant recipients changed as the patients were treated with immunosuppressants and antivirals to ward off graft rejection and infections, the researchers identified a certain pattern of change.

"Strong compositional dynamics are observed at the onset of the drug therapy as the virome composition of different individuals converge to a similar, drug-determined state," Quake and his colleagues wrote.

In particular, the plasma levels of anelloviruses increase in response to drug therapy. The levels of those viruses, Quake and his colleagues suggested, could be used to gauge patients' immunocompetence and possibly stratify potential transplant rejecters from non-rejecters.

To describe virome changes during the course of immunosuppressant and antiviral therapy, the researchers collected some 656 plasma samples from 96 solid-organ transplant recipients over time.

The patients in the cohort were treated according to a standard protocol — typically a tacrolimus-based regimen for the adults — and received high doses of the drugs initially and then lower doses of the drugs as the risk of rejection and infection declined. The 24 pediatric patients were treated with a cyclosporine-based regimen, and were only given antivirals if they tested positive for CMV.

Quake and his colleagues isolated cell-free DNA from the patients' plasma samples and sequenced it on the Illumina HiSeq platform.

To narrow in on the portion derived from the microbiome, the researchers mapped the non-human reads using Blast to a database of 1,401 viral, 1,980 bacterial, and 32 fungal genomes. About 2 percent of the reads were non-human.

Using GRAMMy, a maximum-likelihood estimation-based tool that draws on Blast sequence similarity data, the researchers examined the relative abundance of species and found that viruses were more abundant than bacteria and fungi, and that single-stranded DNA viruses were more common than double-stranded DNA viruses. Indeed, one family, the Anelliviridae, accounted for nearly 70 percent of the population.

Focusing on the 47 adult patients treated with the immunosuppressant tacrolimus, the researchers found that the dose of the drug affected microbiome composition — though just the virome portion.

In particular, when the patients received a high dose of the immunosuppressant and antivirals, the virome was dominated by anelloviridae. Lower doses of the drugs were linked to higher levels of herpesvirales and caudovirales.

This, the researchers noted, is "not surprising" as the antiviral valganciclovir is meant to control CMV infections, and CMV is a herpes virus.

They also compared transplant patients' viromes to the viromes of nine healthy individuals. The patients' viromes resembled those of the healthy patients during minimal drug exposure. The high-drug exposure samples, the researchers found, are distinct from both those from healthy individuals and the low-drug exposure samples.

"[We] find that the composition of the virome for patients that are subject to the same drug therapy converges to a similar state," Quake and his colleagues said.

Then, as the patients were taken off high doses of the drugs, the researchers observed the opposite effects: the levels of anelloviridae fell and herpesvirale and caudovirale levels rose.

The levels of annellovirus in the plasma, the researchers noted, appeared to correlate with immunocompetence and graft rejection episodes.

They compared time-normalized anellovirus load for non-rejecting patients to those from patients suffering a mild rejection event and those undergoing a severe rejection event, as determined through biopsies. From this, they found that time-normalized loads of annellovirus were significantly lower for patients with higher rejection risks.

"The observation of a lower-than-average burden of anelloviruses in patients that suffer from a rejection episode is indicative of insufficient immunosuppression in this subgroup of patients, even though these patients were subject to the immunosuppressant levels prescribed per protocol," Quake and his colleagues said.

They added that "there would be value" in developing an assay that measures immunocompetence, and suggested that anellovirus burden could be a marker of such immunocompetence.