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. 2001 May;75(9):4195-207.
doi: 10.1128/JVI.75.9.4195-4207.2001.

Identification and antigenicity of broadly cross-reactive and conserved human immunodeficiency virus type 1-derived helper T-lymphocyte epitopes

C C Wilson  1 , B Palmer, S Southwood, J Sidney, Y Higashimoto, E Appella, R Chesnut, A Sette, B D Livingston
Affiliations

Identification and antigenicity of broadly cross-reactive and conserved human immunodeficiency virus type 1-derived helper T-lymphocyte epitopes

C C Wilson et al. J Virol. 2001 May.

Abstract

Human immunodeficiency virus (HIV)-specific helper T lymphocytes (HTL) play a key role in the immune control of HIV type 1 (HIV-1) infection, and as such are an important target of potential HIV-1 vaccines. In order to identify HTL epitopes in HIV-1 that might serve as vaccine targets, conserved HIV-1-derived peptides bearing an HLA-DR binding supermotif were tested for binding to a panel of the most representative HLA-DR molecules. Eleven highly cross-reactive binding peptides were identified: three in Gag and eight in Pol. Lymphoproliferative responses to this panel of peptides, as well as to the HIV-1 p24 and p66 proteins, were evaluated with a cohort of 31 HIV-1-infected patients. All 11 peptides were recognized by peripheral blood mononuclear cells from multiple HIV-infected donors. Many of the responsive HIV-infected subjects showed recognition of multiple peptides, indicating that HIV-1-specific T-helper responses may be broadly directed in certain individuals. A strong association existed between recognition of the parental recombinant HIV-1 protein and the corresponding HTL peptides, suggesting that these peptides represent epitopes that are processed and presented during the course of HIV-1 infection. Lastly, responses to the supermotif peptides were mediated by CD4(+) T cells and were restricted by major histocompatibility complex class II molecules. The epitopes described herein are potentially important components of HIV-1 therapeutic and prophylactic vaccines.

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Figures

FIG. 1
FIG. 1
The amino acid sequences of Gag, Pol, Nef, Rev, Tat, Vif, Vpr, and Vpu were scanned for the presence of 15-amino-acid peptides containing the HLA-DR supermotif. Conserved peptides were tested for HLA-DR binding affinity in a sequential panel of HLA-DR binding assays.
FIG. 2
FIG. 2
Percentages of individuals projected to present the indicated number of HLA-DR–epitope combinations in a composite population, derived from gene frequencies in Asian, black, European Caucasian, and North American Caucasian populations (black bars). Also shown on the right axis is the cumulative plot of percent projected population coverage (open circles).
FIG. 3
FIG. 3
Proliferative responses to supermotif HIV-1 HTL epitope peptides. Individual proliferative responses of 22 HIV-1-infected donors and 13 uninfected donors to 11 highly cross-reactive HLA-DR binding HIV-1 peptides, 3 derived from HIV-1 Gag sequences (A), 3 from HIV-1 Pol integrase sequences (B), and 5 from Pol p66 sequences (C), in a 6-day proliferation assay are shown. Proliferative responses to each of the 11 HIV-1 supermotif peptides are depicted as separate points in terms of S.I., with the mean for each group depicted as a solid bar. The number of HIV+ donors that significantly responded to each peptide is listed below the figure. A significant proliferative response to the supermotif peptides was defined based on responses of HIV− control donors, with an S.I. of ≥2 considered significant for all peptides except Gag 171 (S.I. ≥ 2.3) and Pol peptides 335 and 915 (S.I. ≥ 2.8).
FIG. 4
FIG. 4
Analysis of HLA-DR restriction and functional frequencies of HIV-1 HTL supertype peptide-specific CD4+ T cells. (A) Blocking of UH22 PBMC proliferation to the peptides using specific anti-HLA-DR MAb. (B) Lymphoproliferative responses of PBMCs from HIV+ donor UH22 to HIV-1 p24 protein and two Gag supertype epitope peptides contained within the p24 sequence (Gag 294 and 298). The corresponding S.I. are indicated above each bar. The frequencies of CD4+ lymphocytes from donor UH22 producing IFN-γ in response to p24 protein or the Gag peptides both in fresh PBMCs (C) and following in vitro expansion of PBMCs with p24 antigen (D) are depicted.
FIG. 5
FIG. 5
Proliferative responses of PBMCs of HIV-1+ HTL epitope peptide responders (R), HIV-1+ HTL epitope peptide nonresponders (NR), and uninfected donors (HIV-) to recombinant HIV-1 p24 and p66 protein antigens. PBMCs from 22 HIV-1-infected donors (13 of whom had significant proliferative responses to 1 or more of the 11 supermotif HIV-1 HTL peptides and 9 of whom failed to respond to any of the peptides tested) and 13 uninfected donors were tested for their ability to proliferate in response to recombinant HIV-1 p24 and p66 proteins. The mean S.I. for each group is depicted in the figure as a solid line, and the mean S.I. and median S.I. for each group are shown numerically below the figure. P values for differences between each group (Mann-Whitney test) are shown at the top of the figure.
FIG. 6
FIG. 6
Recognition of HIV-1 HTL supertype epitope peptides by HIV-infected donors selected for responses to both recombinant HIV-1 p24 and p66 proteins. Recognition of one or more supertype peptides, based on lymphoproliferation, is compared between an unselected group of 22 HIV+ donors and a group of 13 HIV+ donors selected by the presence of significant lymphoproliferative responses to the two parental proteins, HIV-1 p24 and p66, using the following criteria: S.I. > 5; net cpm > 1,000. Responses are compared for groups of peptides contained within a given HIV-1 protein and for the set of 11 peptides as a whole.
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