Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness.

Autor: Iyer SS; 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., Bibollet-Ruche F; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Sherrill-Mix S; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Learn GH; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Plenderleith L; Institute of Evolutionary Biology, and Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom., Smith AG; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Barbian HJ; 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., Russell RM; 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., Gondim MV; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Bahari CY; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Shaw CM; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Li Y; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Decker T; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Haynes BF; 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., Shaw GM; 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., Sharp PM; Institute of Evolutionary Biology, and Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom., Borrow P; Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom., Hahn BH; 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.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2017 Jan 24; Vol. 114 (4), pp. E590-E599. Date of Electronic Publication: 2017 Jan 09.
DOI: 10.1073/pnas.1620144114
Abstrakt: 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 (IC 50 ) 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.
Competing Interests: The authors declare no conflict of interest.
Databáze: MEDLINE
Externí odkaz: