title: Differences in the Selection Bottleneck between Modes of Sexual Transmission Influence the Genetic Composition of the HIV-1 Founder Virus.
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.
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Damien C
authors.initials: DC
authors.lastname: Tully
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Colin B
authors.initials: CB
authors.lastname: Ogilvie
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Batorsky
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: David J
authors.initials: DJ
authors.lastname: Bean
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Power
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Musie
authors.initials: M
authors.lastname: Ghebremichael
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Hunter E
authors.initials: HE
authors.lastname: Bedard
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Adrianne D
authors.initials: AD
authors.lastname: Gladden
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Seese
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Molly A
authors.initials: MA
authors.lastname: Amero
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Lane
authors.affiliation: Division of Infectious Disease, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Graham
authors.initials: G
authors.lastname: McGrath
authors.affiliation: Division of Infectious Disease, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Suzane B
authors.initials: SB
authors.lastname: Bazner
authors.affiliation: The Fenway Institute, Fenway Health, Boston, Massachusetts, United States of America.
authors.forename: Jake
authors.initials: J
authors.lastname: Tinsley
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Niall J
authors.initials: NJ
authors.lastname: Lennon
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Henn
authors.affiliation: Faculty of Health Sciences, Simon Fraser University, Vancouver, British Columbia, Canada.
authors.forename: Zabrina L
authors.initials: ZL
authors.lastname: Brumme
authors.affiliation: Blood Systems Research Institute, San Francisco, California, United States of America.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Norris
authors.affiliation: Division of Infectious Disease, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Rosenberg
authors.affiliation: The Fenway Institute, Fenway Health, Boston, Massachusetts, United States of America.
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Mayer
authors.affiliation: HIV Clinic Praxis, Jessen, Berlin, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Jessen
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Sergei L
authors.initials: SL
authors.lastname: Kosakovsky Pond
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.|Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.|Heinrich-Pette-Institut, Hamburg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Altfeld
authors.affiliation: Microsoft Research, Redmond, Washington, United States of America.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Carlson
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
mesh_terms: D019143:Evolution, Molecular; D014644:Genetic Variation; D016679:Genome, Viral; D015699:HIV Envelope Protein gp120 / Q000235:genetics; D015658:HIV Infections / Q000635:transmission*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008297:Male; D008962:Models, Theoretical; D016133:Polymerase Chain Reaction; D012641:Selection, Genetic / Q000235:genetics
chemical_list: D015699:HIV Envelope Protein gp120