Reversion and T cell escape mutations compensate the fitness loss of a CD8+ T cell escape mutant in their cognate transmitted/founder virus.

Hongshuo Song,Alan S Perelson,Kevin Wiehe,Bhavna Hora,Nilu Goonetilleke,Tanmoy Bhattacharya,Feng Gao,Shilpa S Iyer,Michael K P Liu,Andrew J Mcmichael,Hui Li

doi:10.1371/journal.pone.0102734

Abstract

Immune escape mutations that revert back to the consensus sequence frequently occur in newly HIV-1-infected individuals and have been thought to render the viruses more fit. However, their impact on viral fitness and their interaction with other immune escape mutations have not been evaluated in the background of their cognate transmitted/founder (T/F) viral genomes. To precisely determine the role of reversion mutations, we introduced reversion mutations alone or together with CD8+ T cell escape mutations in their unmodified cognate T/F viral genome and determined their impact on viral fitness in primary CD4+ T cells. Two reversion mutations, V247I and I64T, were identified in Gag and Tat, respectively, but neither had measurable effect on the fitness of their cognate T/F virus. The V247I and G248A mutations that were detected before and concurrently with the potent T cell escape mutation T242N, respectively, were selected by early T cell responses. The V247I or the G248A mutation alone partially restored the fitness loss caused by the T242N mutation. Together they could fully restore the fitness of the T242N mutant to the T/F level. These results demonstrate that the fitness loss caused by a T cell escape mutation could be compensated by preexisting or concurrent reversion and other T cell escape mutations. Our findings indicate that the overall viral fitness is modulated by the complex interplay among T cell escape, compensatory and reversion mutations to maintain the balance between immune escape and viral replication capacity.

Highlights

The mutations selected in previous donors often revert back to the consensus sequence after the viruses are transmitted into a new host [1,2,3,4,5,6,7,8,9]
These results were in agreement with previous studies, which reported that the G248A mutation alone caused partial loss of the T cell recognition, while the T242N mutation led to a complete escape from the T cell responses targeting the TW10 epitope [5,9,25,37,38]
The NI mutant was 2364% less fit than the T/F virus (p = 0.02) and the NA mutant was 2463% less fit than the T/F virus (p = 0.02). These results demonstrated that the V247I or G248A mutation alone could partially restore the fitness loss caused by the T242N mutation in the TW10 epitope, but only both together could fully compensate the fitness cost due to the T242N mutation as previously demonstrated [25]

Summary

Introduction

The mutations selected in previous donors often revert back to the consensus sequence after the viruses are transmitted into a new host [1,2,3,4,5,6,7,8,9]. The fitness impact of reversion mutations has not been evaluated in their cognate or heterologous viral genomes It generally takes more than a year for the reversion mutations to fully replace the transmitted virus population in the new hosts [5,10,11,12] and some reversions only transiently occur in the viral population [13]. These observations suggest that reversion may not generally render their cognate transmitted/founder (T/F) viruses significantly more fit.

Methods

Results

Conclusion