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

PLoS Pathogens

Philip J. Norris¹  Matthew R. Henn²  Niall J. Lennon²  Sergei L. Kosakovsky Pond³  Graham McGrath⁴  Suzane B. Bazner⁴  Eric S. Rosenberg⁴  Zabrina L. Brumme⁵  Heiko Jessen⁶  Todd M. Allen⁷  Marcus Altfeld⁸  Musie Ghebremichael⁹  Aaron M. Seese⁹  Jonathan M. Carlson⁹  Molly A. Amero⁹  Colin B. Ogilvie⁹  Rebecca E. Batorsky⁹  Hunter E. Bedard⁹  Damien C. Tully⁹  Bruce D. Walker⁹  Adrianne D. Gladden⁹  David J. Bean⁹  Kimberly Lane⁹  Karen A. Power⁹  Jake Tinsley^1,10  Kenneth H. Mayer^1,10 

[1] Blood Systems Research Institute, San Francisco, California, United States of America;Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America;Department of Medicine, University of California San Diego, La Jolla, California, United States of America;Division of Infectious Disease, Massachusetts General Hospital, Boston, Massachusetts, United States of America;Faculty of Health Sciences, Simon Fraser University, Vancouver, British Columbia, Canada;HIV Clinic Praxis, Jessen, Berlin, Germany;Heinrich-Pette-Institut, Hamburg, Germany;Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America;Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America;The Fenway Institute, Fenway Health, Boston, Massachusetts, United States of America

关键词: HIV-1;    Viral transmission;    infection;    Phylogenetics;    DNA sequence analysis;    Natural selection;    Men who have sex with men;    Genome sequencing;    Microbial genetics;   

DOI  :  10.1371/journal.ppat.1005619

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY