Human cytomegalovirus intrahost evolution—a new avenue for understanding and controlling herpesvirus infections

Renzette, Nicholas; Gibson, Laura; Jensen, Jeffrey D.; Kowalik, Timothy F.

doi:10.1016/j.coviro.2014.08.001

Cited by 70 publications

(52 citation statements)

References 62 publications

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“…Such limited variability may reflect the minimal selection pressure on BKV due to the lack of an effective antiviral immune response in an immunocompromised host. This is consistent with findings in studies evaluating intrahost diversity of other viruses which report increased viral diversity in response to immune pressure and decreased diversity with immunosuppression (35)(36)(37). However, despite the conservation of epitopes, we detected low levels of variants that resulted in amino acid changes in the majority of patient samples.…”

Section: Discussionsupporting

confidence: 81%

Limited Variation in BK Virus T-Cell Epitopes Revealed by Next-Generation Sequencing

et al. 2015

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f BK virus (BKV) infection causing end-organ disease remains a formidable challenge to the hematopoietic cell transplant (HCT) and kidney transplant fields. As BKV-specific treatments are limited, immunologic-based therapies may be a promising and novel therapeutic option for transplant recipients with persistent BKV infection. Here, we describe a whole-genome, deep-sequencing methodology and bioinformatics pipeline that identify BKV variants across the genome and at BKV-specific HLA-A2-, HLA-B0702-, and HLA-B08-restricted CD8 T-cell epitopes. BKV whole genomes were amplified using long-range PCR with four inverse primer sets, and fragmentation libraries were sequenced on the Ion Torrent Personal Genome Machine (PGM). An error model and variant-calling algorithm were developed to accurately identify rare variants. A total of 65 samples from 18 pediatric HCT and kidney recipients with quantifiable BKV DNAemia underwent whole-genome sequencing. Limited genetic variation was observed. The median number of amino acid variants identified per sample was 8 (range, 2 to 37; interquartile range, 10), with the majority of variants (77%) detected at a frequency of <5%. When normalized for length, there was no statistical difference in the median number of variants across all genes. Similarly, the predominant virus population within samples harbored T-cell epitopes similar to the reference BKV strain that was matched for the BKV genotype. Despite the conservation of epitopes, low-level variants in T-cell epitopes were detected in 77.7% (14/18) of patients. Understanding epitope variation across the whole genome provides insight into the virus-immune interface and may help guide the development of protocols for novel immunologic-based therapies.

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Section: Discussionsupporting

confidence: 81%

Limited Variation in BK Virus T-Cell Epitopes Revealed by Next-Generation Sequencing

et al. 2015

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“…1, the relative ratio between intrahost and interhost polymorphisms depends on the frequency distribution of polymorphisms within the intrahost populations. This site frequency spectrum is sensitive to a variety of factors, including the demographic history of the population, which in viruses is likely characterized by severe population size reductions associated with infection, followed by rapid population growth (i.e., population bottlenecks [7]). The frequencies of observed polymorphisms are also shaped by the effects of direct selection, in which the frequencies of mutations directly impacting fitness may be increased or decreased depending upon the beneficial or deleterious effect of the mutation.…”

Section: Resultsmentioning

confidence: 99%

On the Analysis of Intrahost and Interhost Viral Populations: Human Cytomegalovirus as a Case Study of Pitfalls and Expectations

Renzette

Pfeifer

Matuszewski

et al. 2017

J Virol

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Intrahost and interhost assessments of viral diversity are often treated as measures of separate and distinct evolutionary processes, with numerous investigations reporting seemingly incompatible results between the two. For example, in human cytomegalovirus, the nucleotide diversity estimates are 10-fold higher for interhost data, while the number of segregating (i.e., polymorphic) sites is 6-fold lower. These results have been interpreted as demonstrating that sampled intrahost variants are strongly deleterious. In reality, however, these observations are fully consistent with standard population genetic expectations. Here, we analyze published intra-and interhost data sets within this framework, utilizing statistical inference tools to quantify the fitness effects of segregating mutations. Further, we utilize population level simulations to clarify expectations under common evolutionary models. Contrary to common claims in the literature, these results suggest that most observed polymorphisms are likely nearly neutral with regard to fitness and that standard population genetic models in fact well predict observed levels of both intra-and interhost variability.IMPORTANCE With the increasing number of evolutionary virology studies examining both intrahost and interhost patterns of genomic variation, a number of seemingly incompatible results have emerged, revolving around the far greater level of observed intrahost than interhost variation. This has led many authors to suggest that the great majority of sampled within-host polymorphisms are strongly deleterious. Here, we demonstrate that there is in fact no incompatibility of these results and, indeed, that the vast majority of sampled within-host variation is likely neutral. These results thus represent a major shift in the current view of observed viral variation.KEYWORDS human cytomegalovirus, interhost diversity, intrahost diversity, population genetics T he majority of evolutionary studies in the virus literature are divided into those examining intrahost data and those examining interhost data. Broadly speaking, intrahost studies deeply sample viral diversity from a limited number of biological samples (e.g., plasma, urine, or saliva), while interhost studies sample viral diversity from a large number of hosts, but with a shallow perspective of variation within each host. These studies are often treated as separate analyses of viral diversity. For example, studies of intrahost human cytomegalovirus (HCMV) populations report per-site nucleotide diversity values of ϳ0.002, with approximately 160,000 segregating (i.e., polymorphic) sites in the ϳ235,000-bp genome, while analyses of interhost data report

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“…While our study did not identify a difference in detectable CD4 or CD8 T cell responses in CNS compared to non-CNS affected infants due to the small cohort, others have shown evidence of immunopathology in mouse [74] and human fetus [75] models. These and other mechanisms intrinsic to or affecting the developing immune system, along with viral immune evasion [76] or genomic evolution [14], perturb the dynamic virus-host interaction to favor persistent viral replication or severe disease in early life.…”

Section: Discussionmentioning

confidence: 99%

“…Compared to adults, infants with congenital CMV infection have less frequently detectable CMV pp65-specific CD4 T cells and lower frequencies of CD8 T cells capable of cytotoxic, chemotaxis, and multiple simultaneous functions, all in the setting of persistent detectable CMV DNA in the peripheral blood. Moreover, recent studies show that CMV genome populations are highly variable between tissue compartments [14], necessitating plasticity of immune responses within the host. The implication of these findings is that an effective CMV vaccine targeting young children would need to accommodate specific features of adaptive immunity in this age group.…”

Section: Discussionmentioning

confidence: 99%

“…Such approaches require that the candidate vaccine induce potent CMV-specific neutralizing antibodies and/or cell-mediated immune responses in infants that correlate with control of viral replication or protection from disease, persist in long-term memory, and are evaluable in clinical trials [11-13]. Moreover, these responses must continuously adapt to the large diversity and rapid evolution of CMV populations within distinct host tissue compartments [14]. …”

Section: Introductionmentioning

confidence: 99%

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Reduced Frequencies of Polyfunctional CMV-Specific T Cell Responses in Infants with Congenital CMV Infection

et al. 2015

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Human cytomegalovirus intrahost evolution—a new avenue for understanding and controlling herpesvirus infections

Cited by 70 publications

References 62 publications

Limited Variation in BK Virus T-Cell Epitopes Revealed by Next-Generation Sequencing

Limited Variation in BK Virus T-Cell Epitopes Revealed by Next-Generation Sequencing

On the Analysis of Intrahost and Interhost Viral Populations: Human Cytomegalovirus as a Case Study of Pitfalls and Expectations

Reduced Frequencies of Polyfunctional CMV-Specific T Cell Responses in Infants with Congenital CMV Infection

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