Modelling and in vitro testing of the HIV-1 Nef fitness landscape

Author:

Barton John P12,Rajkoomar Erasha3,Mann Jaclyn K3,Murakowski Dariusz K1ORCID,Toyoda Mako4,Mahiti Macdonald4,Mwimanzi Phillip4,Ueno Takamasa45,Chakraborty Arup K12,Ndung’u Thumbi2367

Affiliation:

1. Departments of Chemical Engineering, Physics, and Chemistry, Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA

2. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, MA, USA

3. HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa

4. Center for AIDS Research, Kumamoto University, Kumamoto, Japan

5. International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan

6. Africa Health Research Institute, Durban, South Africa

7. Max Planck Institute for Infection Biology, Chariteplatz, D-10117 Berlin, Germany

Abstract

AbstractAn 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.

Funder

National Research Foundation of South Africa

DELTAS Africa Initiative

Wellcome Trust

Publisher

Oxford University Press (OUP)

Subject

Virology,Microbiology

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