Author:
Iyer Shilpa S.,Bibollet-Ruche Frederic,Sherrill-Mix Scott,Learn Gerald H.,Plenderleith Lindsey,Smith Andrew G.,Barbian Hannah J.,Russell Ronnie M.,Gondim Marcos V. P.,Bahari Catherine Y.,Shaw Christiana M.,Li Yingying,Decker Timothy,Haynes Barton F.,Shaw George M.,Sharp Paul M.,Borrow Persephone,Hahn Beatrice H.
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.
Funder
HHS | National Institutes of Health
Publisher
Proceedings of the National Academy of Sciences
Reference90 articles.
1. UNAIDS (2016) Global AIDS Update 2016. Available at www.unaids.org/sites/default/files/media_asset/global-AIDS-update-2016_en.pdf. Accessed December 21, 2016.
2. HIV Transmission
3. Genital inflammation, immune activation and risk of sexual HIV acquisition;Passmore;Curr Opin HIV AIDS,2016
4. HIV and mucosal barrier interactions: consequences for transmission and pathogenesis
5. HIV-host interactions: Implications for vaccine design;Haynes;Cell Host Microbe,2016
Cited by
125 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献