Modelling and in vitro testing of the HIV-1 Nef fitness landscape
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vez029.pdf
Description
Published version
Size
685 KB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Barton, John P
Rajkoomar, Erasha
Mann, Jaclyn K
Murakowski, Dariusz K
Toyoda, Mako
Mahiti, Macdonald
Mwimanzi, Phillip
Ueno, Takamasa
Chakraborty, Arup K
Ndung’u, Thumbi
Date Issued
2019
Journal
Virus Evolution
Publisher
Oxford University Press (OUP)
Version
Final published version
Abstract
An effective vaccine is urgently required to curb the HIV-1 epidemic. We have previously described an approach to model the fitness landscape of several HIV-1 proteins, and have validated the results against experimental and clinical data. The fitness landscape may be used to identify mutation patterns harmful to virus viability, and consequently inform the design of immunogens that can target such regions for immunological control. Here we apply such an analysis and complementary experiments to HIV-1 Nef, a multifunctional protein which plays a key role in HIV-1 pathogenesis. We measured Nef-driven replication capacities as well as Nef-mediated CD4 and HLA-I down-modulation capacities of thirty-Two different Nef mutants, and tested model predictions against these results. Furthermore, we evaluated the models using 448 patient-derived Nef sequences for which several Nef activities were previously measured. Model predictions correlated significantly with Nef-driven replication and CD4 down-modulation capacities, but not HLA-I down-modulation capacities, of the various Nef mutants. Similarly, in our analysis of patient-derived Nef sequences, CD4 down-modulation capacity correlated the most significantly with model predictions, suggesting that of the tested Nef functions, this is the most important in vivo. Overall, our results highlight how the fitness landscape inferred from patient-derived sequences captures, at least in part, the in vivo functional effects of mutations to Nef. However, the correlation between predictions of the fitness landscape and measured parameters of Nef function is not as accurate as the correlation observed in past studies for other proteins. This may be because of the additional complexity associated with inferring the cost of mutations on the diverse functions of Nef.
MIT Department
Massachusetts Institute of Technology. Department of Chemical Engineering
Massachusetts Institute of Technology. Department of Physics
Massachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Ragon Institute of MGH, MIT and Harvard
Terms of Use
Creative Commons Attribution 4.0 International license
Persistent DSpace Link
DOI of Published Version
10.1093/ve/vez029
https://doi.org/10.1093/ve/vez029
