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. 2004 Mar;78(5):2187-200.
doi: 10.1128/jvi.78.5.2187-2200.2004.

Consistent cytotoxic-T-lymphocyte targeting of immunodominant regions in human immunodeficiency virus across multiple ethnicities

Nicole Frahm  1 , B T Korber, C M Adams, J J Szinger, R Draenert, M M Addo, M E Feeney, K Yusim, K Sango, N V Brown, D SenGupta, A Piechocka-Trocha, T Simonis, F M Marincola, A G Wurcel, D R Stone, C J Russell, P Adolf, D Cohen, T Roach, A StJohn, A Khatri, K Davis, J Mullins, P J R Goulder, B D Walker, C Brander
Affiliations

Consistent cytotoxic-T-lymphocyte targeting of immunodominant regions in human immunodeficiency virus across multiple ethnicities

Nicole Frahm et al. J Virol. 2004 Mar.

Abstract

Although there is increasing evidence that virus-specific cytotoxic-T-lymphocyte (CTL) responses play an important role in the control of human immunodeficiency virus (HIV) replication in vivo, only scarce CTL data are available for the ethnic populations currently most affected by the epidemic. In this study, we examined the CD8(+)-T-cell responses in African-American, Caucasian, Hispanic, and Caribbean populations in which clade B virus dominates and analyzed the potential factors influencing immune recognition. Total HIV-specific CD8(+)-T-cell responses were determined by enzyme-linked immunospot assays in 150 HIV-infected individuals by using a clade B consensus sequence peptide set spanning all HIV proteins. A total of 88% of the 410 tested peptides were recognized, and Nef- and Gag-specific responses dominated the total response for each ethnicity in terms of both breadth and magnitude. Three dominantly targeted regions within these proteins that were recognized by >90% of individuals in each ethnicity were identified. Overall, the total breadth and magnitude of CD8(+)-T-cell responses correlated with individuals' CD4 counts but not with viral loads. The frequency of recognition for each peptide was highly correlated with the relative conservation of the peptide sequence, the presence of predicted immunoproteasomal cleavage sites within the C-terminal half of the peptide, and a reduced frequency of amino acids that impair binding of optimal epitopes to the restricting class I molecules. The present study thus identifies factors that contribute to the immunogenicity of these highly targeted and relatively conserved sequences in HIV that may represent promising vaccine candidates for ethnically heterogeneous populations.

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Figures

FIG. 1.
FIG. 1.
HLA allele frequencies in different ethnicities. HLA class I allele distributions are shown for HLA-A (A), HLA-B (B), and HLA-Cw (C) alleles. Frequencies are shown for 73 African-Americans (open bars), 75 Caucasians (lightly shaded bars), 47 Hispanics (darkly shaded bars), and 80 West Indians (solid bars). The asterisks mark alleles that show significant differences among ethnicities (Fisher's exact test; P < 0.001).
FIG. 2.
FIG. 2.
CTL responses in four ethnic groups are distributed over the entire HIV genome and cluster in immunodominant regions. The total HIV-specific CD8+-T-cell activities for 59 African-Americans, 26 Caucasians, 44 Hispanics, and 21 West Indians were tested using an OLP set of 410 peptides. The frequencies of recognition for each single peptide in the four ethnicities are shown. The horizontal box at the bottom indicates the HIV proteins spanned by the OLPs.
FIG. 3.
FIG. 3.
Effective antiretroviral treatment reduces CTL activity. ELISpot responses are shown for 61 untreated (−Tx; squares) and 89 treated (+Tx; diamonds) subjects. The latter were further divided into 42 non-treatment-suppressed (viral load [VL] > 200; triangles) and 44 treatment-suppressed (VL ≤ 200; inverted triangles) individuals. Shown are the breadth of responses (number of targeted peptides) (A) and the total magnitude (number of SFC per million PBMCs) (B) for the different groups. The thick lines represent the median values for each group. P values were determined by Mann-Whitney tests.
FIG. 4.
FIG. 4.
CTL activity correlates with CD4 counts but not viral loads in untreated subjects. Association between the number of targeted peptides and the viral load (VL) (A) or CD4 count (B) and association between the total magnitude of the CD8+-T-cell response and viral load (C) or CD4 count (D) are shown for 61 untreated subjects. P values were determined by Spearman rank tests. Correlation in panel B remains significant when subjects with CD4 counts of >1,000 cells/μl are excluded (P = 0.0085). CD4 counts were available for 59 subjects.
FIG. 5.
FIG. 5.
The frequency of peptide recognition is inversely correlated with peptide entropy. The number of subjects recognizing each peptide and the peptide entropy for each of 410 OLPs were correlated (P < 0.0001; Spearman rank test). Reactivity is shown by the open bars; entropy is shown by the solid bars. nat, natural unit; aa, amino acid.
FIG. 6.
FIG. 6.
(A to C) Influence of entropy (A), fraction of forbidden amino acids (AA) (B), and proteasomal cleavage scores (C) on the frequency of recognition of OLPs. Entropy and the fraction of forbidden amino acids correlate inversely (P < 0.0001) and cleavage scores correlate positively (P = 0.0003) with the frequency of recognition. (D) Favorable conditions for high recognition are defined as low entropy, few forbidden amino acids, and high cleavage scores; scores are divided into high and low categories at the median. Stepwise multiple-regression analyses indicated that each of the three variables contributed significantly to the model, that there were no second-order effects based on combinations of the variables, and that there was no benefit in using a quadratic model rather than a linear model to fit the data.
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References

    1. Addo, M. M., X. G. Yu, A. Rathod, D. Cohen, R. L. Eldridge, D. Strick, M. N. Johnston, C. Corcoran, A. G. Wurcel, C. A. Fitzpatrick, M. E. Feeney, W. R. Rodriguez, N. Basgoz, R. Draenert, D. R. Stone, C. Brander, P. J. R. Goulder, E. S. Rosenberg, M. Altfeld, and B. D. Walker. 2003. Comprehensive epitope analysis of human immunodeficiency virus type 1 (HIV-1)-specific T-cell responses directed against the entire expressed HIV-1 genome demonstrate broadly directed responses, but no correlation to viral load. J. Virol. 77:2081-2092. - PMC - PubMed
    1. Altfeld, M., M. M. Addo, R. Shankarappa, P. K. Lee, T. M. Allen, X. G. Yu, A. Rathod, J. D. Harlow, K. O'Sullivan, M. N. Johnston, P. J. R. Goulder, J. I. Mullins, E. S. Rosenberg, C. Brander, B. T. Korber, and B. D. Walker. 2003. Enhanced detection of human immunodeficiency virus type 1-specific T-cell responses to highly variable regions by using peptides based on autologous virus sequences. J. Virol. 77:7330-7340. - PMC - PubMed
    1. Altfeld, M., T. Allen, X. G. Yu, M. N. Johnston, D. Agrawal, B. T. Korber, D. C. Montefiori, D. H. O'Connor, B. T. Davis, P. K. Lee, E. L. Maier, J. D. Harlow, P. J. R. Goulder, C. Brander, E. S. Rosenberg, and B. D. Walker. 2002. HIV-1 superinfection despite broadly directed pre-existing CD8+ T cell responses containing replication of the primary virus. Nature 420:434-439. - PubMed
    1. Altfeld, M., J. van Lunzen, N. Frahm, X. G. Yu, C. Schneider, R. L. Eldridge, M. E. Feeney, D. Meyer-Olson, H. J. Stellbrink, and B. D. Walker. 2002. Expansion of pre-existing, lymph node-localized CD8+ T cells during supervised treatment interruptions in chronic HIV-1 infection. J. Clin. Investig. 109:837-843. - PMC - PubMed
    1. Amara, R. R., F. Villinger, J. D. Altman, S. L. Lydy, S. P. O'Neil, S. I. Staprans, D. C. Montefiori, Y. Xu, J. G. Herndon, L. S. Wyatt, M. A. Candido, N. L. Kozyr, P. L. Earl, J. M. Smith, H. L. Ma, B. D. Grimm, M. L. Hulsey, J. Miller, H. M. McClure, J. M. McNicholl, B. Moss, and H. L. Robinson. 2001. Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine. Science 292:69-74. - PubMed

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