Detecting Selection in the HIV-1 Genome during Sexual Transmission Events.

David Seifert,Thomas Klimkait,Huldrych F Günthard,Sabine Yerly,Dominique L Braun,Beda Joos,Corinna S Oberle,Herbert Kuster,Niko Beerenwinkel,Corinne D Schenkel,Karin J Metzner,Christina Grube,Vincent Aubert,Jürg Böni

doi:10.3390/v14020406

Abstract

Little is known about whether and how variation in the HIV-1 genome affects its transmissibility. Assessing which genomic features of HIV-1 are under positive or negative selection during transmission is challenging, because very few virus particles are typically transmitted, and random genetic drift can dilute genetic signals in the recipient virus population. We analyzed 30 transmitter–recipient pairs from the Zurich Primary HIV Infection Study and the Swiss HIV Cohort Study using near full-length HIV-1 genomes. We developed a new statistical test to detect selection during transmission, called Selection Test in Transmission (SeTesT), based on comparing the transmitter and recipient virus population and accounting for the transmission bottleneck. We performed extensive simulations and found that sensitivity of detecting selection during transmission is limited by the strong population bottleneck of few transmitted virions. When pooling individual test results across patients, we found two candidate HIV-1 genomic features for affecting transmission, namely amino acid positions 3 and 18 of Vpu, which were significant before but not after correction for multiple testing. In summary, SeTesT provides a general framework for detecting selection based on genomic sequencing data of transmitted viruses. Our study shows that a higher number of transmitter–recipient pairs is required to improve sensitivity of detecting selection.

Highlights

Introduction distributed under the terms andWhile major achievements have been made in containing the HIV/AIDS pandemic, the worldwide prevalence of people living with human immunodeficiency virus type 1(HIV-1) is continuing to increase [1]
We developed a statistical test called Selection Test in Transmission (SeTesT) on the basis of a probabilistic model for detecting selection during viral transmission using viral next-generation sequencing (NGS) data of transmitter–recipient pairs (Figure 2)
We found that a significant obstacle in detecting transmission selection is the strong population bottleneck (Supplementary Materials, Section S4), while read coverage of the transmitted viral population does not improve statistical power beyond 100–1000 reads

Summary

Introduction

While major achievements have been made in containing the HIV/AIDS pandemic, the worldwide prevalence of people living with human immunodeficiency virus type 1. HIV-1 is transmitted via body fluids containing blood, semen, vaginal secretions, or breast milk. The main route of transmission occurs via sexual conditions of the Creative Commons. 80% of transmissions are due to heterosexual transmission, with over 90% occurring in the resource-limited world [2]. The human body presents multiple barriers during and after transmission that HI virions have to overcome to establish a persistent infection [3]. Crossing the genital and rectal mucosa presents itself as the first physical barrier. HIV-1 has to evade innate and adaptive immune responses and enter a target cell in order to replicate [3,4]

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