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. 2014 Dec 22;2(1):46-58.
doi: 10.1016/j.ebiom.2014.12.009. eCollection 2015 Jan.

CD8(+) T-cell Cytotoxic Capacity Associated with Human Immunodeficiency Virus-1 Control Can Be Mediated through Various Epitopes and Human Leukocyte Antigen Types

Stephen A Migueles  1 , Daniel Mendoza  1 , Matthew G Zimmerman  1 , Kelly M Martins  1 , Sushila A Toulmin  1 , Elizabeth P Kelly  1 , Bennett A Peterson  1 , Sarah A Johnson  1 , Eric Galson  1 , Kate O Poropatich  1 , Andy Patamawenu  1 , Hiromi Imamichi  1 , Alexander Ober  1 , Catherine A Rehm  1 , Sara Jones  2 , Claire W Hallahan  3 , Dean A Follmann  3 , Mark Connors  1
Affiliations

CD8(+) T-cell Cytotoxic Capacity Associated with Human Immunodeficiency Virus-1 Control Can Be Mediated through Various Epitopes and Human Leukocyte Antigen Types

Stephen A Migueles et al. EBioMedicine. .

Abstract

Understanding natural immunologic control over Human Immunodeficiency Virus (HIV)-1 replication, as occurs in rare long-term nonprogressors/elite controllers (LTNP/EC), should inform the design of efficacious HIV vaccines and immunotherapies. Durable control in LTNP/EC is likely mediated by highly functional virus-specific CD8(+) T-cells. Protective Human Leukocyte Antigen (HLA) class I alleles, like B*27 and B*57, are present in most, but not all LTNP/EC, providing an opportunity to investigate features shared by their HIV-specific immune responses. To better understand the contribution of epitope targeting and conservation to immune control, we compared the CD8(+) T-cell specificity and function of B*27/57(neg) LTNP/EC (n = 23), B*27/57(pos) LTNP/EC (n = 23) and B*27/57(neg) progressors (n = 13). Fine mapping revealed 11 previously unreported immunodominant responses. Although B*27/57(neg) LTNP/EC did not target more highly conserved epitopes, their CD8(+) T-cell cytotoxic capacity was significantly higher than progressors. Similar to B*27/57(pos) LTNP/EC, this superior cytotoxicity was mediated by preferential expansion of immunodominant responses and lysis through the predicted HLA. These findings suggest that increased CD8(+) T-cell cytotoxic capacity is a common mechanism of control in most LTNP/EC regardless of HLA type. They also suggest that potent cytotoxicity can be mediated through various epitopes and HLA molecules and could, in theory, be induced in most people.

Keywords: CD8+ T cells; Cytotoxic capacity; Epitope specificity; Immune control; Long-term nonprogressors/elite controllers.

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Figures

Fig. 1
Fig. 1
HIV-specific CD8+ T-cell responses of B*27/57neg LTNP/EC are similar to those of B*27/57pos LTNP/EC. Frequencies of IFN-γ+CD69+CD8+ T-cells in response to 15-mer peptide pools spanning HIV-1 (A) Nef, (B) Gag, (C) Pol and (D) total (sum of A–C) are shown for B*27/57neg LTNP/EC (n = 23), B*27/57pos LTNP/EC (n = 23) and B*27/57neg viremic progressors (n = 13). Upon further mapping, (E) the sum of the frequencies of IFN-γ+CD69+CD8+ T-cells and (F) the sum of the numbers of targeted peptides are shown for B*27/57neg LTNP/EC and B*27/57neg viremic progressors. Horizontal lines represent median values. Comparisons were made using the Wilcoxon two-sample test. Only significant p values are shown.
Fig. 2
Fig. 2
Immunodominant responses of both B*27/57neg LTNP/EC and progressors target conserved regions in HIV-1. (A) Prevalence of B*27/57neg LTNP/EC (n = 23, white bars) and B*27/57neg progressors (n = 13, solid gray bars) with significant IFN-γ+CD69+CD8+ T-cell responses above background to individual Gag 15-mers are shown. Trend line connects the Shannon entropy scores for each 15-mer. Block arrows identify sequence positions corresponding to B27/57-restricted Gag epitopes (B27-KK10, B57-IW9, B57-KF11, B57-TW10 and B57-QW9; white) and mapped Gag epitopes targeted by immunodominant CD8+ T-cell responses of B*27/57neg subjects (n = 36, gray). Highly variable regions are shaded. (B) Entropy scores of confirmed and predicted Nef (squares), Gag (triangles) and Pol (diamonds) epitopes targeted by immunodominant CD8+ T-cell responses of B*27/57neg LTNP/EC (open symbols) and progressors (solid gray symbols) are shown. (C) Entropy scores of 1000 pseudo-epitopes in Nef, Gag and Pol compared with those of best-defined (“A list”) epitopes and known B27/57-restricted epitopes from LANL and epitopes recognized by B*27/57neg subjects (non-B27/57) in this study. Horizontal lines represent median values. Comparisons were made using the Wilcoxon two-sample test. Only significant p values are shown as **(p < 0.01).
Fig. 3
Fig. 3
Bulk and per-cell HIV-specific CD8+ T-cell cytotoxic responses of B*27/57neg LTNP/EC exceeded those of progressors and were comparable to those of B*27/57pos LTNP/EC. After 1 h co-incubation, CD8+ T-cell cytotoxic responses measured by (A) GrB target cell activity (circles) and (B) infected CD4+ T-cell elimination (ICE, diamonds) are shown for B*27/57neg LTNP/EC (open symbols, n = 17), B*27/57pos LTNP/EC (solid black symbols, n = 18) and viremic progressors (solid gray symbols, n = 18). Horizontal lines represent median values. Data are representative of three independent experiments. Comparisons were made using the Wilcoxon two-sample test. Only significant p values are shown. Per-cell cytotoxic capacity was assessed in B*27/57neg LTNP/EC (red symbols), B*27/57pos LTNP/EC (black open symbols) and viremic progressors (solid gray symbols) through comparisons of cytotoxicity curves, which were generated by plotting (C) GrB activity and ICE (D) values against the true E/T ratios based upon measurements of IFN-γ+ CD8+ T-cells and p24-expressing targets. Analysis of covariance was used to quantify the differences in GrB activity and ICE among the groups over the shared range of logged E/T ratios.
Fig. 4
Fig. 4
Immunodominant HIV-specific CD8+ T-cell responses preferentially expanded and contributed most significantly to overall cytotoxicity. (A) Representative plots depicting GrB activity after 1-hour co-incubation of LTNP/EC-19 CD8+ T-cells (initially stimulated for 6 days with autologous HIVSF162-infected CD4+ T-cells) with un-infected CD4+ T-cell targets (background), HIVSF162-infected CD4+ T-cell targets, un-infected CD4+ T-cell targets pulsed with an “irrelevant” peptide (elicited no response in cytokine detection assays) and un-infected CD4+ T-cell targets pulsed with the TL9 peptide (LTNP/EC-19's immunodominant epitope in cytokine assays). Numbers in top, right corner correspond to the percentages of the total targets that are GrB substrate+ after 1-hour co-incubation with effectors. (B) Cytotoxic responses were further mapped after co-incubation of CD8+ T-cells with heterologous HIVSF162-infected CD4+ T-cell targets matched at a single HLA locus (overlaid on bars) in 7 B*27/57neg and one representative B*27/57pos LTNP/EC (right bars). Background in response to heterologous un-infected targets was subtracted. For comparison, the fractions of the total IFN-γ response restricted by a particular HLA protein are also shown (left bars). Black bars represent unmapped responses. Data are representative of three independent experiments. (C–D) Cytotoxic responses, measured by (C) GrB activity (circles) or (D) ICE (diamonds) from the 7 B*27/57neg LTNP/EC in (B), were categorized as immunodominant (black symbols, n = 10) or non-immunodominant (gray symbols, n = 11), plotted against the true E/T ratios and compared (see Experimental Procedures).
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