title: Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness.
abstract: Sexual transmission of HIV-1 is an inefficient process, with only one or few variants of the donor quasispecies establishing the new infection. A critical, and as yet unresolved, question is whether the mucosal bottleneck selects for viruses with increased transmission fitness. Here, we characterized 300 limiting dilution-derived virus isolates from the plasma, and in some instances genital secretions, of eight HIV-1 donor and recipient pairs. Although there were no differences in the amount of virion-associated envelope glycoprotein, recipient isolates were on average threefold more infectious (P = 0.0001), replicated to 1.4-fold higher titers (P = 0.004), were released from infected cells 4.2-fold more efficiently (P < 0.00001), and were significantly more resistant to type I IFNs than the corresponding donor isolates. Remarkably, transmitted viruses exhibited 7.8-fold higher IFNα2 (P < 0.00001) and 39-fold higher IFNβ (P < 0.00001) half-maximal inhibitory concentrations (IC50) than did donor isolates, and their odds of replicating in CD4+T cells at the highest IFNα2 and IFNβ doses were 35-fold (P < 0.00001) and 250-fold (P < 0.00001) greater, respectively. Interestingly, pretreatment of CD4+T cells with IFNβ, but not IFNα2, selected donor plasma isolates that exhibited a transmitted virus-like phenotype, and such viruses were also detected in the donor genital tract. These data indicate that transmitted viruses are phenotypically distinct, and that increased IFN resistance represents their most distinguishing property. Thus, the mucosal bottleneck selects for viruses that are able to replicate and spread efficiently in the face of a potent innate immune response.
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.|Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Shilpa S
authors.initials: SS
authors.lastname: Iyer
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Frederic
authors.initials: F
authors.lastname: Bibollet-Ruche
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Scott
authors.initials: S
authors.lastname: Sherrill-Mix
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Gerald H
authors.initials: GH
authors.lastname: Learn
authors.affiliation: Institute of Evolutionary Biology, and Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Plenderleith
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Smith
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.|Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Hannah J
authors.initials: HJ
authors.lastname: Barbian
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.|Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Ronnie M
authors.initials: RM
authors.lastname: Russell
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Marcos V P
authors.initials: MV
authors.lastname: Gondim
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Catherine Y
authors.initials: CY
authors.lastname: Bahari
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Christiana M
authors.initials: CM
authors.lastname: Shaw
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Timothy
authors.initials: T
authors.lastname: Decker
authors.affiliation: Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710.|Department of Medicine, Duke University Medical Center, Durham, NC 27710.|Department of Immunology, Duke University Medical Center, Durham, NC 27710.
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.|Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: George M
authors.initials: GM
authors.lastname: Shaw
authors.affiliation: Institute of Evolutionary Biology, and Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Sharp
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom.
authors.forename: Persephone
authors.initials: P
authors.lastname: Borrow
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; bhahn@upenn.edu.|Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
mesh_terms: D005260:Female; D015658:HIV Infections / Q000276:immunology* / Q000635:transmission*; D015497:HIV-1 / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D007370:Interferon Type I / Q000276:immunology*; D008297:Male; D012661:Semen / Q000821:virology; D044364:Vaginal Douching; D014771:Virion; D014779:Virus Replication
chemical_list: D007370:Interferon Type I
keywords: HIV-1 transmission fitness; HIV-1 transmission pairs; innate immunity; mucosal HIV-1 transmission; type I interferons