Influence of recombination on acquisition and reversion of immune escape and compensatory mutations in HIV-1
OPEN ACCESS
Author / Producer
Date
2016-03
Publication Type
Journal Article
ETH Bibliography
yes
Citations
Altmetric
OPEN ACCESS
Data
Rights / License
Abstract
Following transmission, HIV-1 adapts in the new host by acquiring mutations that allow it to escape from the host immune response at multiple epitopes. It also reverts mutations associated with epitopes targeted in the transmitting host but not in the new host. Moreover, escape mutations are often associated with additional compensatory mutations that partially recover fitness costs. It is unclear whether recombination expedites this process of multi-locus adaptation. To elucidate the role of recombination, we constructed a detailed population dynamics model that integrates viral dynamics, host immune response at multiple epitopes through cytotoxic T lymphocytes, and viral evolution driven by mutation, recombination, and selection. Using this model, we compute the expected waiting time until the emergence of the strain that has gained escape and compensatory mutations against the new host's immune response, and reverted these mutations at epitopes no longer targeted. We find that depending on the underlying fitness landscape, shaped by both costs and benefits of mutations, adaptation proceeds via distinct dominant pathways with different effects of recombination, in particular distinguishing escape and reversion. When adaptation at a single epitope is involved, recombination can substantially accelerate immune escape but minimally affects reversion. When multiple epitopes are involved, recombination can accelerate or inhibit adaptation depending on the fitness landscape. Specifically, recombination tends to delay adaptation when a purely uphill fitness landscape is accessible at each epitope, and accelerate it when a fitness valley is associated with each epitope. Our study points to the importance of recombination in shaping the adaptation of HIV-1 following its transmission to new hosts, a process central to T cell-based vaccine strategies.
Permanent link
Publication status
published
External links
Editor
Book title
Journal / series
Volume
14
Pages / Article No.
11 - 25
Publisher
Elsevier
Event
Edition / version
Methods
Software
Geographic location
Date collected
Date created
Subject
Cytotoxic T lymphocytes; Fitness landscape; Immune escape; Multi-locus adaptation; Waiting time; Fitness landscape
Organisational unit
03584 - Bonhoeffer, Sebastian / Bonhoeffer, Sebastian