Drivers of within-host genetic diversity in acute infections of viruses.

Maoz Gelbart,Ya’Ara Ben-Ari,Sheri Harari,Orna Mor,Dana Wolf,Talia Kustin,Michal Mandelboim,Pleuni S Pennings,Adi Stern,Anice C Lowen

doi:10.1371/journal.ppat.1009029

Abstract

Genetic diversity is the fuel of evolution and facilitates adaptation to novel environments. However, our understanding of what drives differences in the genetic diversity during the early stages of viral infection is somewhat limited. Here, we use ultra-deep sequencing to interrogate 43 clinical samples taken from early infections of the human-infecting viruses HIV, RSV and CMV. Hundreds to thousands of virus templates were sequenced per sample, allowing us to reveal dramatic differences in within-host genetic diversity among virus populations. We found that increased diversity was mostly driven by presence of multiple divergent genotypes in HIV and CMV samples, which we suggest reflect multiple transmitted/founder viruses. Conversely, we detected an abundance of low frequency hyper-edited genomes in RSV samples, presumably reflecting defective virus genomes (DVGs). We suggest that RSV is characterized by higher levels of cellular co-infection, which allow for complementation and hence elevated levels of DVGs.

Highlights

Viruses are among the fastest evolving entities on earth
We sought to characterize what leads to differences in the genetic diversity of different viruses sampled during acute infection
We found that the DNA virus CMV was less diverse, most likely since it has a lower mutation rate than the RNA viruses human immunodeficiency virus (HIV) and respiratory syncytial virus (RSV)

Summary

Introduction

Thanks to short generation times, large population sizes and high mutation rates, viruses and in particular RNA viruses rapidly accumulate genetic diversity. This genetic diversity is key to successful adaptation of viruses to novel challenges such as the immune system and drugs [1]. The short time window following virus transmission determines whether viruses are able to establish a successful infection, and when this occurs, the initial infection is termed acute infection. These first few days to weeks of viral replication may go unnoticed, since they sometimes precede symptoms. Much remains unknown regarding the genetic diversity of viruses during acute infection: how many different genotypes found an infection? What is the role of standing genetic diversity in escape from the immune system, or evasion of drugs? And how does cell-autonomous innate immunity affect the genetic diversity of a viral population? To answer these questions, deep population sequencing is necessary, i.e., accurate sequencing that maintains high yield and allows sequencing a large number of viral genomes, and allows the study of haplotypes rather than isolated mutational events

Methods

Results

Discussion

Conclusion