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Abstract
Human cytomegalovirus (HCMV) is an important opportunistic pathogen in allogeneic haematopoietic stem cell transplant (HSCT) recipients. High-throughput sequencing of target-enriched libraries was performed to characterise the diversity of HCMV strains present in this high-risk group. Forty-four HCMV-DNA-positive plasma specimens (median viral input load 321 IU per library) collected at defined time points from 23 HSCT recipients within 80 days of transplantation were sequenced. The genotype distribution for 12 hypervariable HCMV genes and the number of HCMV strains present (i.e. single- vs. multiple-strain infection) were determined for 29 samples from 16 recipients. Multiple-strain infection was observed in seven of these 16 recipients, and five of these seven recipients had the donor (D)/recipient (R) HCMV-serostatus combination D + R + . A very broad range of genotypes was detected, with an intrahost composition that was generally stable over time. Multiple-strain infection was not associated with particular virological or clinical features, such as altered levels or duration of antigenaemia, development of acute graft-versus-host disease or increased mortality. In conclusion, despite relatively low viral plasma loads, a high frequency of multiple-strain HCMV infection and a high strain complexity were demonstrated in systematically collected clinical samples from this cohort early after HSCT. However, robust evaluation of the pathogenic role of intrahost viral diversity and multiple-strain infection will require studies enrolling larger numbers of recipients.
Highlights
Despite excellent screening strategies and antiviral treatment regimens applied prophylactically or pre-emptively, human cytomegalovirus (HCMV) remains a significant pathogen following allogeneic haematopoietic stem cell transplantation (HSCT) [1,2,3,4]
Prior to the advent of high-throughput sequencing (HTS), many genotyping studies based on polymerase chain reaction (PCR) and Sanger sequencing of single hypervariable genes were aimed at linking clinical outcome parameters to aspects of viral diversity, but were compromised by limitations in understanding strain complexity within individuals [20,21,22,23,24]
Data sets meeting the quality criteria for genotyping and strain enumeration were obtained from 24 samples from 14 HSCT recipients
Summary
Despite excellent screening strategies and antiviral treatment regimens applied prophylactically or pre-emptively, human cytomegalovirus (HCMV) remains a significant pathogen following allogeneic haematopoietic stem cell transplantation (HSCT) [1,2,3,4]. The diversity of HCMV strains is apparent in a subset of hypervariable genes, each of which presents several stable genotypes, and interstrain recombination during HCMV evolution has generated huge numbers of strains worldwide [11,12,13,14,15,16]. Reactivation of multiple latent HCMV strains as well as exogenous reinfection with one or more strains can contribute to viral diversity within individuals [17,18,19]. Prior to the advent of high-throughput sequencing (HTS), many genotyping studies based on polymerase chain reaction (PCR) and Sanger sequencing of single hypervariable genes were aimed at linking clinical outcome parameters to aspects of viral diversity, but were compromised by limitations in understanding strain complexity within individuals [20,21,22,23,24]
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