Differences in the Selection Bottleneck between Modes of Sexual Transmission Influence the Genetic Composition of the HIV-1 Founder Virus.

Damien C Tully,Heiko Jessen,Kenneth H Mayer,Colin B Ogilvie,Bruce D Walker,Adrianne D Gladden,Marcus Altfeld,David J Bean,Molly A Amero,Jonathan M Carlson,Graham Mcgrath,Sergei L Kosakovsky Pond,Niall J Lennon,Kimberly Lane,Philip J Norris,Karen A Power,Hunter E Bedard,Todd M Allen,Matthew R Henn,Eric S Rosenberg,Musie Ghebremichael,Zabrina L Brumme,Rebecca Batorsky ,Suzane Bazner ,Aaron Seese ,Jake P Tinsley

doi:10.1371/journal.ppat.1005619

Abstract

Due to the stringent population bottleneck that occurs during sexual HIV-1 transmission, systemic infection is typically established by a limited number of founder viruses. Elucidation of the precise forces influencing the selection of founder viruses may reveal key vulnerabilities that could aid in the development of a vaccine or other clinical interventions. Here, we utilize deep sequencing data and apply a genetic distance-based method to investigate whether the mode of sexual transmission shapes the nascent founder viral genome. Analysis of 74 acute and early HIV-1 infected subjects revealed that 83% of men who have sex with men (MSM) exhibit a single founder virus, levels similar to those previously observed in heterosexual (HSX) transmission. In a metadata analysis of a total of 354 subjects, including HSX, MSM and injecting drug users (IDU), we also observed no significant differences in the frequency of single founder virus infections between HSX and MSM transmissions. However, comparison of HIV-1 envelope sequences revealed that HSX founder viruses exhibited a greater number of codon sites under positive selection, as well as stronger transmission indices possibly reflective of higher fitness variants. Moreover, specific genetic “signatures” within MSM and HSX founder viruses were identified, with single polymorphisms within gp41 enriched among HSX viruses while more complex patterns, including clustered polymorphisms surrounding the CD4 binding site, were enriched in MSM viruses. While our findings do not support an influence of the mode of sexual transmission on the number of founder viruses, they do demonstrate that there are marked differences in the selection bottleneck that can significantly shape their genetic composition. This study illustrates the complex dynamics of the transmission bottleneck and reveals that distinct genetic bottleneck processes exist dependent upon the mode of HIV-1 transmission.

Highlights

The global spread of HIV-1 has been fueled predominantly by HSX transmission, with men who have sex with men (MSM) representing a second major risk group [1]
We identified a number of residues within Envelope that behave in a risk-dependent manner and could be key for HIV-1 transmission
These novel insights improve our understanding of the HIV-1 transmission bottleneck and underscore the differential selective pressures that founder viruses within the two major transmission risk groups are subjected to

Summary

Introduction

The global spread of HIV-1 has been fueled predominantly by HSX transmission, with MSM representing a second major risk group [1]. In 80% of HSX transmissions a single founder virus is responsible for productive clinical infection [7, 14,15,16,17,18], whereas among MSM the incidence of multi-variant transmission is reported to be higher with up to 40% of infections established by multiple viral variants [14, 19] These data, coupled with epidemiological data illustrating differential risks of infection based on the route of exposure [20], suggest that the mode of transmission influences the selection of the viral variant(s) establishing systemic infection

Methods

Results

Discussion

Conclusion