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

Abstract

Human cytomegalovirus (HCMV) is exquisitely adapted to the human host, and much research has focused on its evolution over long timescales spanning millennia. Here, we review recent data exploring the evolution of the virus on much shorter timescales, on the order of days or months. We describe the intrahost genetic diversity of the virus isolated from humans, and how this diversity contributes to HCMV spatiotemporal evolution. We propose mechanisms to explain the high levels of intrahost diversity and discuss how this new information may shed light on HCMV infection and pathogenesis.

Figure 1. HCMV Intrahost genetic diversity as compared to RNA viruses

Viral intrahost diversities are represented as circles with the diameters, drawn on a log scale, representing reported values of diversity. The genetic diversity of HCMV populations is comparable to those of RNA viruses, an unexpected result given that HCMV is a large dsDNA virus. Values were obtained from [16] and references therein. Abbreviations are as follows: WNV: West Nile Virus, HCMV: human cytomegalovirus, DENV: dengue virus, HCV: hepatitis C virus. Scale bar represents the diameter of a genetic diversity value of 0.1%.

Figure 2. Models of HCMV Diversity and Evolution

Panel A shows an example of the structure of an HCMV intrahost population. Minor variants in the population are distributed around a central sequence. Most variants are only a few mutational steps away from this central sequence. This distribution of sequences is known as a star phylogeny and can be formed by the high levels of replication associated with primary infection, where most de novo mutations will be rare and shared by few members of the population. Panel B shows a more complicated population structure which could result from reinfection. In this example, the blue and red dashed lines represent strains, with minor variants radiating from the central sequence of each strain. The genetic distance between strains is significantly greater than the genetic distance of minor variants from their respective central sequences. Panel C depicts a model of HCMV evolution derived from congenital infection data. In this model, the peripheral blood harbors the most diverse sub-population of HCMV within the body. During dissemination to distal compartments, the viral population can rapidly evolve, either due to natural selection or stochastic mechanisms such as population bottlenecks, leading to populations in the distal tissues or organs being genetically differentiated from the peripheral blood compartment. This phenomenon is known as compartmentalization. The populations in the distal compartments are also less genetically diverse than those of the peripheral blood. Once HCMV has disseminated to compartments or if the virus remains in the peripheral blood, the populations become relatively stable and many mutations remain at similar frequencies over time.