Persistent Survival of Prevalent Clonotypes within an Immunodominant HIV Gag-Specific CD8+ T Cell Response

St. Vincent's Centre for Applied Medical Research, University of New South Wales, Sydney, New South Wales, Australia.
The Journal of Immunology (Impact Factor: 4.92). 01/2011; 186(1):359-71. DOI: 10.4049/jimmunol.1001807
Source: PubMed


CD8(+) T cells play a significant role in the control of HIV replication, yet the associated qualitative and quantitative factors that determine the outcome of infection remain obscure. In this study, we examined Ag-specific CD8(+) TCR repertoires longitudinally in a cohort of HLA-B*2705(+) long-term nonprogressors with chronic HIV-1 infection using a combination of molecular clonotype analysis and polychromatic flow cytometry. In each case, CD8(+) T cell populations specific for the immunodominant p24 Gag epitope KRWIILGLNK (KK10; residues 263-272) and naturally occurring variants thereof, restricted by HLA-B*2705, were studied at multiple time points; in addition, comparative data were collected for CD8(+) T cell populations specific for the CMV pp65 epitope NLVPMVATV (NV9; residues 495-503), restricted by HLA-A*0201. Dominant KK10-specific clonotypes persisted for several years and exhibited greater stability than their contemporaneous NV9-specific counterparts. Furthermore, these dominant KK10-specific clonotypes exhibited cross-reactivity with antigenic variants and expressed significantly higher levels of CD127 (IL-7Rα) and Bcl-2. Of note, we also found evidence that promiscuous TCR α-chain pairing associated with alterations in fine specificity for KK10 variants could contribute to TCR β-chain prevalence. Taken together, these data suggest that an antiapoptotic phenotype and the ability to cross-recognize variant epitopes contribute to clonotype longevity and selection within the peripheral memory T cell pool in the presence of persistent infection with a genetically unstable virus.

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Available from: Miles P Davenport, Aug 01, 2014
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    • "Through a process known as TCR clonotype selection, certain clonotypes may become more dominant along T cell differentiation [14-16] or throughout the time course of infection [17]. Persistence of human virus-specific T cell clonotypes over several years has been demonstrated in humans with various viral infections: influenza [18], herpes simplex virus [19,20], EBV [21], cytomegalovirus (CMV) [14] and human immunodeficiency virus (HIV) [22]. Recently, Klarenbeek and colleagues [23] addressed the question of whether the clonal repertoire that is established during the early phase of infections against CMV and EBV is maintained over extended periods of time. "
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    ABSTRACT: Persistent viruses are kept in check by specific lymphocytes. The clonal T cell receptor (TCR) repertoire against Epstein-Barr virus (EBV), once established following primary infection, exhibits a robust stability over time. However, the determinants contributing to this long-term persistence are still poorly characterized. Taking advantage of an in vivo clinical setting where lymphocyte homeostasis was transiently perturbed, we studied EBV antigen-specific CD8 T cells before and after non-myeloablative lympho-depleting chemotherapy of melanoma patients. Despite more advanced T cell differentiation, patients T cells showed clonal composition comparable to healthy individuals, sharing a preference for TRBV20 and TRBV29 gene segment usage and several co-dominant public TCR clonotypes. Moreover, our data revealed the presence of relatively few dominant EBV antigen-specific T cell clonotypes, which mostly persisted following transient lympho-depletion (TLD) and lymphocyte recovery, likely related to absence of EBV reactivation and de novo T cell priming in these patients. Interestingly, persisting clonotypes frequently co-expressed memory/homing-associated genes (CD27, IL7R, EOMES, CD62L/SELL and CCR5) supporting the notion that they are particularly important for long-lasting CD8 T cell responses. Nevertheless, the clonal composition of EBV-specific CD8 T cells was preserved over time with the presence of the same dominant clonotypes after non-myeloablative chemotherapy. The observed clonotype persistence demonstrates high robustness of CD8 T cell homeostasis and reconstitution.
    PLoS ONE 10/2013; 8(10):e78686. DOI:10.1371/journal.pone.0078686 · 3.23 Impact Factor
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    • "Given the very large numbers of possible peptide epitopes that could be presented by the MHC to T-cell receptors, it has been argued that a single TCR may recognize multiple epitopes (Mason, 1998). These theoretical considerations are supported by data in LTNP demonstrating TCR cross-reactivity by HLA-B * 2705-restricted KK10 clones (Almeida et al., 2009; van Bockel et al., 2011; Chen et al., 2012) and HLA-B * 5701/03-restricted clones (Gillespie et al., 2002; Turnbull et al., 2006; Simons et al., 2008) toward known viral variants. An example of an immunodominant clonotype that bound both wild-type and L268M KK10 peptides is shown in Figure 2, as originally described in van Bockel et al. (2011). "
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    ABSTRACT: Long-term non-progressors (LTNP) were identified after 10-15 years of the epidemic, and have been the subject of intense investigation ever since. In a small minority of cases, infection with nef/3'LTR deleted attenuated viral strains allowed control over viral replication. A common feature of LTNP is the readily detected proliferation of CD4 T cells in vitro, in response to p24. In some cases, the responding CD4 T cells have cytotoxic effector function and may target conserved p24 epitopes, similar to the CD8 T cells described below. LTNP may also carry much lower HIV DNA burden in key CD4 subsets, presumably resulting from lower viral replication during primary infection. Some studies, but not others, suggest that LTNP have CD4 T cells that are relatively resistant to HIV infection in vitro. One possible mechanism may involve up-regulation of the cell cycle regulator p21/waf in CD4 T cells from LTNP. Delayed progression in Caucasian LTNP is also partly associated with heterozygosity of the ∆32 CCR5 allele, probably through decreased expression of CCR5 co-receptor on CD4 T cells. However, in approximately half of Caucasian LTNP, two host genotypes, namely HLA-B57 and HLA-B27, are associated with viral control. Immunodominant CD8 T cells from these individuals target epitopes in p24 that are highly conserved, and escape mutations have significant fitness costs to the virus. Furthermore, recent studies have suggested that these CD8 T cells from LTNP, but not from HLA-B27 or HLA-B57 progressors, can cross-react with intermediate escape mutations, preventing full escape via compensatory mutations. Humoral immunity appears to play little part in LTNP subjects, since broadly neutralizing antibodies are rare, even amongst slow progressors. Recent genome wide comparisons between LTNP and progressors have confirmed the HLA-B57, HLA-B27 and delta32 CCR5 allelic associations, plus indicated a role for HLA-C/KIR interactions, but have not revealed any new genotypes so far.
    Frontiers in Immunology 04/2013; 4:95. DOI:10.3389/fimmu.2013.00095
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    • "Individuals possessing the “protective” HLA-allele B*2705 have the ability to rearrange the TCR to produce high affinity clonotypes specific to certain viral epitopes essential for HIV-1 fitness (van Bockel et al., 2011). In agreement with a number of other studies, we have observed a high representation of alleles associated with delayed disease progression in our cohort of LTNP with undetectable viral load (Guergnon et al., 2012). "
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    ABSTRACT: Complex mechanisms underlying the maintenance of fully functional, proliferative, HIV-1-specific T-cell responses involve processes from early T-cell development through to the final stages of T-cell differentiation and antigen recognition. Virus-specific proliferative CD4 and CD8 T-cell responses, important for the control of infection, are observed in some HIV-1 patients during early stages of disease, and are maintained in long-term non-progressing subjects. In the vast majority of HIV-1 patients, full immune functionality is lost when proliferative HIV-1-specific T-cell responses undergo a variable progressive decline throughout the course of chronic infection. This appears irreparable despite administration of potent combination antiretroviral therapy, which to date is non-curative, necessitating life-long administration and the development of effective, novel, therapeutic interventions. While a sterilizing cure, involving clearance of virus from the host, remains a primary aim, a "functional cure" may be a more feasible goal with considerable impact on worldwide HIV-1 infection. Such an approach would enable long-term co-existence of host and virus in the absence of toxic and costly drugs. Effective immune homeostasis coupled with a balanced response appropriately targeting conserved viral antigens, in a manner that avoids hyperactivation and exhaustion, may prove to be the strongest correlate of durable viral control. This review describes novel concepts underlying full immune functionality in the context of HIV-1 infection, which may be utilized in future strategies designed to improve upon existing therapy. The aim will be to induce long-term non-progressor or elite controller status in every infected host, through immune-mediated control of viremia and reduction of viral reservoirs, leading to lower HIV-1 transmission rates.
    Frontiers in Immunology 03/2013; 4:58. DOI:10.3389/fimmu.2013.00058
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