Elite Controllers and Long-term Nonprogressors: Models for HIV Vaccine Development?

Okulicz, Jason F.

doi:10.4172/2155-6113.1000139

Cited by 12 publications

(9 citation statements)

References 49 publications

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“…In the present study, we evaluated parameters related to the immune activation state of T cells and the balance of Th17/Treg cells in HICs with different levels of viral replication control to evaluate immunologic factors related to the better infection control. Although most HIVinfected individuals present an immunological dysregulation characterized by alterations in the frequency of T cell subsets, excessive and systemic immune activation/inflammation and changes in the intestinal mucosa [2,4,60], HICs have a more preserved immunological system and represent a model of spontaneous infection control [61][62][63].…”

Section: Discussionmentioning

confidence: 99%

HIV-1 elite controllers present a high frequency of activated regulatory T and Th17 cells

et al. 2020

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Section: Discussionmentioning

confidence: 99%

HIV-1 elite controllers present a high frequency of activated regulatory T and Th17 cells

et al. 2020

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“…HICs are a rare population of HIV-1-infected individuals who represent the best existing model of spontaneous viral control [ 2 , 59 , 60 ]. Although the mechanisms responsible for this control are not fully understood, studies show that these individuals have a differentiated and more effective CTL response [ 61 ], which should be then reflected in greater genetic pressure on their viral quasispecies, mainly in immunodominant regions.…”

Section: Discussionmentioning

confidence: 99%

Next-generation sequencing analyses of the emergence and maintenance of mutations in CTL epitopes in HIV controllers with differential viremia control

et al. 2018

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BackgroundDespite the low level of viral replication in HIV controllers (HICs), studies have reported viral mutations related to escape from cytotoxic T-lymphocyte (CTL) response in HIV-1 plasma sequences. Thus, evaluating the dynamics of the emergence of CTL-escape mutants in HICs reservoirs is important for understanding viremia control. To analyze the HIV-1 mutational profile and dynamics of CTL-escape mutants in HICs, we selected 11 long-term non-progressor individuals and divided them into the following groups: (1) viremic controllers (VCs; n = 5) and (2) elite controllers (ECs; n = 6). For each individual, we used HIV-1 proviral DNA from PBMCs related to earliest (VE) and latest (VL) visits to obtain gag and nef sequences using the Illumina HiSeq system. The consensus of each mapped gene was used to assess viral divergence, and next-generation sequencing data were employed to identify SNPs and variations within and flanking CTL epitopes.ResultsDivergence analysis showed higher values for nef compared to gag among the HICs. EC and VC groups showed similar divergence rates for both genes. Analysis of the number of SNPs showed that VCs present more variability in both genes. Synonymous/non-synonymous mutation ratios were < 1 for gag among ECs and for nef among ECs and VCs, exhibiting a predominance of non-synonymous mutations. Such mutations were observed in regions encoding CTL-restricted epitopes in all individuals. All ECs presented non-synonymous mutations in CTL epitopes but generally at low frequency (< 1%); all VCs showed a high number of mutations, with significant frequency changes between VE and VL visits. A higher frequency of internal mutations was observed for gag epitopes, with significant changes across visits compared to Nef epitopes, indicating a pattern associated with differential genetic pressure.ConclusionsThe high genetic conservation of HIV-1 gag and nef among ECs indicates that the higher level of viremia control restricts the evolution of both genes. Although viral replication levels in HICs are low or undetectable, all individuals exhibited CTL epitope mutations in proviral gag and nef variants, indicating that potential CTL escape mutants are present in HIC reservoirs and that situations leading to a disequilibrium of the host-virus relationship can result in the spread of CTL-escape variants.Electronic supplementary materialThe online version of this article (10.1186/s12977-018-0444-z) contains supplementary material, which is available to authorized users.

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“…Understanding the mechanism of viral control achieved in LTNPs with protective MHC-I alleles provides insights for developing functional cure and T cell-mediated vaccine against HIV ( 16 , 44 , 45 ). Several T cell vaccine strategies focus on using evolutionarily conserved regions in HIV genome as immunogens, with the promise that escape mutations in the conserved regions will incur higher fitness cost ( 46 – 50 ).…”

Section: Discussionmentioning

confidence: 99%

Effects of Mutations on Replicative Fitness and Major Histocompatibility Complex Class I Binding Affinity Are Among the Determinants Underlying Cytotoxic-T-Lymphocyte Escape of HIV-1 Gag Epitopes

Zhang

Dai

et al. 2017

mBio

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Certain “protective” major histocompatibility complex class I (MHC-I) alleles, such as B*57 and B*27, are associated with long-term control of HIV-1 in vivo mediated by the CD8+ cytotoxic-T-lymphocyte (CTL) response. However, the mechanism of such superior protection is not fully understood. Here we combined high-throughput fitness profiling of mutations in HIV-1 Gag, in silico prediction of MHC-peptide binding affinity, and analysis of intraperson virus evolution to systematically compare differences with respect to CTL escape mutations between epitopes targeted by protective MHC-I alleles and those targeted by nonprotective MHC-I alleles. We observed that the effects of mutations on both viral replication and MHC-I binding affinity are among the determinants of CTL escape. Mutations in Gag epitopes presented by protective MHC-I alleles are associated with significantly higher fitness cost and lower reductions in binding affinity with respect to MHC-I. A linear regression model accounting for the effect of mutations on both viral replicative capacity and MHC-I binding can explain the protective efficacy of MHC-I alleles. Finally, we found a consistent pattern in the evolution of Gag epitopes in long-term nonprogressors versus progressors. Overall, our results suggest that certain protective MHC-I alleles allow superior control of HIV-1 by targeting epitopes where mutations typically incur high fitness costs and small reductions in MHC-I binding affinity.

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Elite Controllers and Long-term Nonprogressors: Models for HIV Vaccine Development?

Cited by 12 publications

References 49 publications

HIV-1 elite controllers present a high frequency of activated regulatory T and Th17 cells

HIV-1 elite controllers present a high frequency of activated regulatory T and Th17 cells

Next-generation sequencing analyses of the emergence and maintenance of mutations in CTL epitopes in HIV controllers with differential viremia control

Effects of Mutations on Replicative Fitness and Major Histocompatibility Complex Class I Binding Affinity Are Among the Determinants Underlying Cytotoxic-T-Lymphocyte Escape of HIV-1 Gag Epitopes

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