Delineating CD4 dependency of HIV-1: Adaptation to infect low level CD4 expressing target cells widens cellular tropism but severely impacts on envelope functionality
Authors
Beauparlant, DavidRusert, Peter
Magnus, Carsten
Kadelka, Claus
Weber, Jacqueline
Uhr, Therese
Zagordi, Osvaldo
Oberle, Corinna
Duenas-Decamp, Maria J.
Clapham, Paul R.
Metzner, Karin J.
Gunthard, Huldrych F.
Trkola, Alexandra
UMass Chan Affiliations
Program in Molecular MedicineDocument Type
Journal ArticlePublication Date
2017-03-06
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A hallmark of HIV-1 infection is the continuously declining number of the virus' predominant target cells, activated CD4+ T cells. With diminishing CD4+ T cell levels, the capacity to utilize alternate cell types and receptors, including cells that express low CD4 receptor levels such as macrophages, thus becomes crucial. To explore evolutionary paths that allow HIV-1 to acquire a wider host cell range by infecting cells with lower CD4 levels, we dissected the evolution of the envelope-CD4 interaction under in vitro culture conditions that mimicked the decline of CD4high target cells, using a prototypic subtype B, R5-tropic strain. Adaptation to CD4low targets proved to severely alter envelope functions including trimer opening as indicated by a higher affinity to CD4 and loss in shielding against neutralizing antibodies. We observed a strikingly decreased infectivity on CD4high target cells, but sustained infectivity on CD4low targets, including macrophages. Intriguingly, the adaptation to CD4low targets altered the kinetic of the entry process, leading to rapid CD4 engagement and an extended transition time between CD4 and CCR5 binding during entry. This phenotype was also observed for certain central nervous system (CNS) derived macrophage-tropic viruses, highlighting that the functional perturbation we defined upon in vitro adaptation to CD4low targets occurs in vivo. Collectively, our findings suggest that CD4low adapted envelopes may exhibit severe deficiencies in entry fitness and shielding early in their evolution. Considering this, adaptation to CD4low targets may preferentially occur in a sheltered and immune-privileged environment such as the CNS to allow fitness restoring compensatory mutations to occur.Source
PLoS Pathog. 2017 Mar 6;13(3):e1006255. doi: 10.1371/journal.ppat.1006255. eCollection 2017 Mar. Link to article on publisher's siteDOI
10.1371/journal.ppat.1006255Permanent Link to this Item
http://hdl.handle.net/20.500.14038/40321PubMed ID
28264054Related Resources
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Copyright © 2017 Beauparlant et alDistribution License
http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.1371/journal.ppat.1006255
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Except where otherwise noted, this item's license is described as Copyright © 2017 Beauparlant et al