HIV-1 Replication Fitness of HLA-B*57/58:01 CTL Escape Variants Is Restored by the Accumulation of Compensatory Mutations in Gag

Esther F Gijsbers,K Anton Feenstra,Neeltje A Kootstra,Jaap Heringa,Ad C Van Nuenen,Marjon Navis,Hanneke Schuitemaker,Fabrizio Mammano

doi:10.1371/journal.pone.0081235

Abstract

Expression of HLA-B*57 and the closely related HLA-B*58:01 are associated with prolonged survival after HIV-1 infection. However, large differences in disease course are observed among HLA-B*57/58:01 patients. Escape mutations in CTL epitopes restricted by these HLA alleles come at a fitness cost and particularly the T242N mutation in the TW10 CTL epitope in Gag has been demonstrated to decrease the viral replication capacity. Additional mutations within or flanking this CTL epitope can partially restore replication fitness of CTL escape variants. Five HLA-B*57/58:01 progressors and 5 HLA-B*57/58:01 long-term nonprogressors (LTNPs) were followed longitudinally and we studied which compensatory mutations were involved in the restoration of the viral fitness of variants that escaped from HLA-B*57/58:01-restricted CTL pressure. The Sequence Harmony algorithm was used to detect homology in amino acid composition by comparing longitudinal Gag sequences obtained from HIV-1 patients positive and negative for HLA-B*57/58:01 and from HLA-B*57/58:01 progressors and LTNPs. Although virus isolates from HLA-B*57/58:01 individuals contained multiple CTL escape mutations, these escape mutations were not associated with disease progression. In sequences from HLA-B*57/58:01 progressors, 5 additional mutations in Gag were observed: S126N, L215T, H219Q, M228I and N252H. The combination of these mutations restored the replication fitness of CTL escape HIV-1 variants. Furthermore, we observed a positive correlation between the number of escape and compensatory mutations in Gag and the replication fitness of biological HIV-1 variants isolated from HLA-B*57/58:01 patients, suggesting that the replication fitness of HLA-B*57/58:01 escape variants is restored by accumulation of compensatory mutations.

Highlights

HLA class I alleles are associated with the clinical course of HIV-1 infection
To study differences in the Gag protein of virus isolates obtained from HLA-B*57/58:01 progressors and long-term nonprogressors (LTNPs) that may explain the differences in replication kinetics, we compared Gag sequences obtained from various time points during the course of infection (Table 1 and Table S1) using the Sequence Harmony (SH) algorithm [29,30,31]
6 amino acid positions in Gag were identified that showed significant variation in the dominant amino acid between sequences from individuals with or without HLA-B*57/58:01. Among these HLA-B*57/ 58:01 specific amino acid mutations were the HLA-B*57/58:01 associated cytotoxic T lymphocyte (CTL) escape mutations T242N and G248A located in the TW10 epitope and the I147L mutation in the IW9 epitope

Summary

Introduction

HLA-B*57 and the closely related HLA-B*58:01 are overrepresented in so called long-term nonprogressors (LTNPs) [1,2,3,4,5,6,7]. Individuals carrying these HLA alleles exert strong cytotoxic T lymphocyte (CTL) responses against conserved viral regions such as Gag, resulting in immunological control of HIV-1 replication and a slower disease progression [8,9,10,11,12,13]. The escape mutations allow evasion of the CTL response, viral escape is not always associated with disease progression.

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Results

Conclusion