A Molecular Basis for the Control of Preimmune Escape Variants by HIV-Specific CD8+ T Cells

Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, Wales, UK.
Immunity (Impact Factor: 21.56). 03/2013; 38(3):425-36. DOI: 10.1016/j.immuni.2012.11.021
Source: PubMed


The capacity of the immune system to adapt to rapidly evolving viruses is a primary feature of effective immunity, yet its molecular basis is unclear. Here, we investigated protective HIV-1-specific CD8(+) T cell responses directed against the immunodominant p24 Gag-derived epitope KK10 (KRWIILGLNK263-272) presented by human leukocyte antigen (HLA)-B(∗)2705. We found that cross-reactive CD8(+) T cell clonotypes were mobilized to counter the rapid emergence of HIV-1 variants that can directly affect T cell receptor (TCR) recognition. These newly recruited clonotypes expressed TCRs that engaged wild-type and mutant KK10 antigens with similar affinities and almost identical docking modes, thereby accounting for their antiviral efficacy in HLA-B(∗)2705(+) individuals. A protective CD8(+) T cell repertoire therefore encompasses the capacity to control TCR-accessible mutations, ultimately driving the development of more complex viral escape variants that disrupt antigen presentation.

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    • "These differences among CTL clonotypes in potency and cross-reactivity of recognition of HIV-1 and its variants7 are in line with the T cell receptor (TCR)-based modulation of effector cell subsets10 and suggest that the fine specificity of TCRs may modulate their antiviral function78111213. Although a co-crystalized X-ray structure has recently been reported for a single clonotype interacting with the human leukocyte antigen (HLA) B*2705-restricted epitope KK10 (KRWIILGLNK, Gag aa 263–272)11, the underlying molecular mechanism for clonotypic differences in antiviral efficacy against this and other epitopes has not been fully understood due to the limited availability of co-crystalized structures of the TCR-peptide-MHC complexes. "
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    ABSTRACT: Immune control of viral infections is modulated by diverse T cell receptor (TCR) clonotypes engaging peptide-MHC class I complexes on infected cells, but the relationship between TCR structure and antiviral function is unclear. Here we apply in silico molecular modeling with in vivo mutagenesis studies to investigate TCR-pMHC interactions from multiple CTL clonotypes specific for a well-defined HIV-1 epitope. Our molecular dynamics simulations of viral peptide-HLA-TCR complexes, based on two independent co-crystal structure templates, reveal that effective and ineffective clonotypes bind to the terminal portions of the peptide-MHC through similar salt bridges, but their hydrophobic side-chain packings can be very different, which accounts for the major part of the differences among these clonotypes. Non-specific hydrogen bonding to viral peptide also accommodates greater epitope variants. Furthermore, free energy perturbation calculations for point mutations on the viral peptide KK10 show excellent agreement with in vivo mutagenesis assays, with new predictions confirmed by additional experiments. These findings indicate a direct structural basis for heterogeneous CTL antiviral function.
    Scientific Reports 02/2014; 4:4087. DOI:10.1038/srep04087 · 5.58 Impact Factor
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    • "Due to the known correlation between viral escape mutations and the decline of respective CD8 T cell responses [10,27-31] we focused on declining CD8 T cell responses over the disease course. In contrast to other studies we did not focus on individuals expressing protective HLA alleles [9,11-16] or exclusively on acute HIV infection [10,18,29,30,38]. We purposefully included untreated, chronically infected individuals because viral escape occurs also in this stage of infection and this group has not been studied as extensively as acutely infected individuals [28,39]. "
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    ABSTRACT: HIV evades CD8 T cell mediated pressure by viral escape mutations in targeted CD8 T cell epitopes. A viral escape mutation can lead to a decline of the respective CD8 T cell response. Our question was what happened after the decline of a CD8 T cell response and - in the case of viral escape - if a new CD8 T cell response towards the mutated antigen could be generated in a population not selected for certain HLA alleles. We studied 19 antiretroviral-naïve HIV-1 infected individuals with different disease courses longitudinally. A median number of 12 (range 2-24) CD8 T cell responses towards Gag and Nef were detected per study subject. A total of 30 declining CD8 T cell responses were studied in detail and viral sequence analyses showed amino acid changes in 25 (83%) of these. Peptide titration assays and definition of optimal CD8 T cell epitopes revealed 12 viral escape mutations with one de-novo response (8%). The de-novo response, however, showed less effector functions than the original CD8 T cell response. In addition we identified 4 shifts in immunodominance. For one further shift in immunodominance, the mutations occurred outside the optimal epitope and might represent processing changes. Interestingly, four adaptations to the virus (the de-novo response and 3 shifts in immunodominance) occurred in the group of chronically infected progressors. None of the subjects with adaptation to the changing virus carried the HLA alleles B57, B*58:01 or B27. Our results show that CD8 T cell responses adapt to the mutations of HIV. However it was limited to only 20% (5 out of 25) of the epitopes with viral sequence changes in a cohort not expressing protective HLA alleles.
    PLoS ONE 12/2013; 8(12):e80045. DOI:10.1371/journal.pone.0080045 · 3.23 Impact Factor
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    • "Lessons learned from EC are also influencing cure strategies involving gene therapy. The class I HLA alleles B57 and B27 are the most recognized genetic elements associated with HIV control, and recently several studies have demonstrated that HLA-B27 and B57 restricted TCR clonotypes from EC have superior ability to suppress HIV-1 replication in vitro (Chen et al., 2012), greater cross-reactivity to epitope variants (Chen et al., 2012; Ladell et al., 2013) and enhanced loading and delivery of perforin in comparison to HLA-B27 and B57 restricted TCR clonotypes form non-controllers (Chen et al., 2012). Researchers are now examining the possibility to modulate the TCR repertoire of patients not carrying protective HLAs, or having immunodominant non-effective TCR clonotypes by TCR gene transfer (Varela-Rohena et al., 2008; Barsov et al., 2011; Hofmann et al., 2011). "
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    ABSTRACT: Accumulating data generated from persons who naturally control HIV without the need for antiretroviral treatment has led to significant insights into the possible mechanisms of durable control of AIDS virus infection. At the center of this control is the HIV-specific CD8 T cell response, and the basis for this CD8-mediated control is gradually being revealed. Genome wide association studies coupled with HLA sequence data implicate the nature of the HLA-viral peptide interaction as the major genetic factor modulating durable control of HIV, but host genetic factors account for only around 20% of the variability in control. Other factors including specific functional characteristics of the TCR clonotypes generated in vivo, targeting of vulnerable regions of the virus that lead to fitness impairing mutations, immune exhaustion, and host restriction factors that limit HIV replication all have been shown to additionally contribute to control. Moreover, emerging data indicate that the CD8(+) T cell response may be critical for attempts to purge virus infected cells following activation of the latent reservoir, and thus lessons learned from elite controllers (ECs) are likely to impact the eradication agenda. On-going efforts are also needed to understand and address the role of immune activation in disease progression, as it becomes increasingly clear that durable immune control in ECs comes at a cost. Taken together, the research achievements in the attempt to unlock the mechanisms behind natural control of HIV will continue to be an important source of insights and ideas in the continuous search after an effective HIV vaccine, and for the attempts to achieve a sterilizing or functional cure in HIV positive patients with progressive infection.
    Frontiers in Immunology 06/2013; 4:162. DOI:10.3389/fimmu.2013.00162
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