Tracking HIV-1 recombination to resolve its contribution to HIV-1 evolution in natural infection

Hongshuo Song,Hyejin Yoon,Peter Hraber,Tanmoy Bhattacharya,Andrew J Mcmichael,Myron S Cohen,Vitaly V Ganusov,Jesus F Salazar-Gonzalez,Fangping Cai,Xiaojun Li,Ethan Romero-Severson,David C Montefiori,Barton F Haynes,Maria G Salazar,George M Shaw,Chunlai Jiang,Brandon F Keele,Shuyi Wang,Beatrice H Hahn,Gayathri Athreya,Nilu Goonetilleke,Bette T Korber ,Elena E Giorgi,Bhavna Hora,Hui Li,Oana Carja,Feng Gao

doi:10.1038/s41467-018-04217-5

Abstract

Recombination in HIV-1 is well documented, but its importance in the low-diversity setting of within-host diversification is less understood. Here we develop a novel computational tool (RAPR (Recombination Analysis PRogram)) to enable a detailed view of in vivo viral recombination during early infection, and we apply it to near-full-length HIV-1 genome sequences from longitudinal samples. Recombinant genomes rapidly replace transmitted/founder (T/F) lineages, with a median half-time of 27 days, increasing the genetic complexity of the viral population. We identify recombination hot and cold spots that differ from those observed in inter-subtype recombinants. Furthermore, RAPR analysis of longitudinal samples from an individual with well-characterized neutralizing antibody responses shows that recombination helps carry forward resistance-conferring mutations in the diversifying quasispecies. These findings provide insight into molecular mechanisms by which viral recombination contributes to HIV-1 persistence and immunopathogenesis and have implications for studies of HIV transmission and evolution in vivo.

Highlights

Recombination in HIV-1 is well documented, but its importance in the low-diversity setting of within-host diversification is less understood
To investigate potential mechanisms for the rapid loss of transmitted/ founder (T/F) viruses and their lineages during early infection, we developed a mathematical model of HIV-1 evolution that includes recombination
We developed a new analytical tool, RAPR, that allows for computationally efficient detection of recombinants in longitudinal samples from recently infected individuals

Summary

Introduction

Recombination in HIV-1 is well documented, but its importance in the low-diversity setting of within-host diversification is less understood. We develop a novel computational tool (RAPR (Recombination Analysis PRogram)) to enable a detailed view of in vivo viral recombination during early infection, and we apply it to near-full-length HIV-1 genome sequences from longitudinal samples. RAPR analysis of longitudinal samples from an individual with well-characterized neutralizing antibody responses shows that recombination helps carry forward resistance-conferring mutations in the diversifying quasispecies. These findings provide insight into molecular mechanisms by which viral recombination contributes to HIV-1 persistence and immunopathogenesis and have implications for studies of HIV transmission and evolution in vivo. Other studies analyzed only a small portion of the viral genome Such shortcomings can bias estimates of the frequencies and evolutionary dynamics of recombinants in vivo

Methods

Results

Conclusion