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. 2003 Jun;77(12):6889-98.
doi: 10.1128/jvi.77.12.6889-6898.2003.

The differential ability of HLA B*5701+ long-term nonprogressors and progressors to restrict human immunodeficiency virus replication is not caused by loss of recognition of autologous viral gag sequences

Stephen A Migueles  1 , Alisha C Laborico, Hiromi Imamichi, W Lesley Shupert, Cassandra Royce, Mary McLaughlin, Linda Ehler, Julia Metcalf, Shuying Liu, Claire W Hallahan, Mark Connors
Affiliations

The differential ability of HLA B*5701+ long-term nonprogressors and progressors to restrict human immunodeficiency virus replication is not caused by loss of recognition of autologous viral gag sequences

Stephen A Migueles et al. J Virol. 2003 Jun.

Abstract

Although the HLA B(*)5701 class I allele is highly overrepresented among human immunodeficiency virus (HIV)-infected long-term nonprogressors (LTNPs), it is also present at the expected frequency (11%) in patients with progressive HIV infection. Whether B57(+) progressors lack restriction of viral replication because of escape from recognition of highly immunodominant B57-restricted gag epitopes by CD8(+) T cells remains unknown. In this report, we investigate the association between restriction of virus replication and recognition of autologous virus sequences in 27 B(*)57(+) patients (10 LTNPs and 17 progressors). Amplification and direct sequencing of single molecules of viral cDNA or proviral DNA revealed low frequencies of genetic variations in these regions of gag. Furthermore, CD8(+) T-cell recognition of autologous viral variants was preserved in most cases. In two patients, responses to autologous viral variants were not demonstrable at one epitope. By using a novel technique to isolate primary CD4(+) T cells expressing autologous viral gene products, it was found that 1 to 13% of CD8(+) T cells were able to respond to these cells by gamma interferon production. In conclusion, escape-conferring mutations occur infrequently within immunodominant B57-restricted gag epitopes and are not the primary mechanism of virus evasion from immune control in B(*)5701(+) HIV-infected patients. Qualitative features of the virus-specific CD8(+) T-cell response not measured by current assays remain the most likely determinants of the differential abilities of HLA B(*)5701(+) LTNPs and progressors to restrict virus replication.

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Figures

FIG.1.
FIG.1.
gag gene sequencing results and alignment with references. Thirty-five reference sequences from the Los Alamos HIV sequence database and sequencing results from 10 B*57+ LTNPs and 17 B*57+ progressors are shown for four regions of Gag that contain known HLA B57-restricted epitopes (highlighted). Peptide numbers (15, 17, 23, and 30) correspond to 20-mers used previously to map the Gag peptide-specific CD8+ T-cell responses in B*57+ patients: 15, residues 141 to 160; 17, residues 161 to 180; 23, residues 231 to 250; 30, residues 301 to 320. Only sequence differences are shown. X, position corresponding to a stop codon; #, position of amino acid whose codon has an ambiguous base. Anchor residues within the epitope that stabilize binding with B57 are located at positions 2 (S, T, and A) and 9 to 11 (W and F).
FIG. 2.
FIG. 2.
The percentages of CD69+ IFN-γ+ CD8+ T cells responding to autologous B cells pulsed with either the consensus sequence (QW9) or mutated (mutQW9) peptides corresponding to codons 308 to 316 in gag. (A) Peptide titration using the consensus sequence peptide (top) and mutated peptide (bottom) in five B*57+ LTNPs (black) and five B*57+ progressors (lime) revealed that the responses to the consensus sequence peptide are typically higher but that the optimal concentration for both peptides is 10 μM. (B) Summary of the CD8+ T-cell responses to QW9 (black) and the mutated peptide (red) for five B*57+ LTNPs and nine B*57+ progressors. Background activity against autologous B cells without the peptide has been subtracted. The results shown are representative of three experiments. Patients are listed in order of increasing plasma viral RNA levels. The autologous sequence at position 312 (position 5 within the epitope) is listed below the patient numbers.
FIG. 3.
FIG. 3.
A summary of the total HIV-specific CD8+ T-cell responses by using two techniques of antigen presentation. The percentages of CD69+ IFN-γ+ CD8+ T cells responding to autologous EBV-transformed B cells infected with vaccinia virus-HIV recombinants (stacked-bar histograms) and autologous primary CD4+ T cells infected with HIVSF162 (blue histograms) for five B*57+ LTNPs and nine B*57+ progressors are shown. Background activity against B cells infected with the control virus vaccinia virus-β-galactosidase or uninfected autologous primary CD4+ T-cell lymphoblasts, respectively, has been subtracted. These results are representative of at least three experiments.
FIG. 4.
FIG. 4.
CD8+ T-cell responses to autologous primary CD4+ T cells expressing autologous virus. (A) By gating on CD3+ lymphocytes, the percentages of primary CD4+ T-cell targets expressing autologous virus are determined by intracellular p24 (Kc57) staining and estimated as the sums of values in the upper left and upper right quadrants. Representative data are shown for two B*57+ patients. (B) The percentages of CD69+ IFN-γ+ CD8+ T cells (upper right quadrant) in response to autologous primary CD4+ T-cell targets expressing autologous virus are shown for the same two B*57+ patients.
FIG. 5.
FIG. 5.
Summary of the total HIV-specific CD8+ T-cell responses by using three techniques of antigen presentation. The percentages of CD69+ IFN-γ+ CD8+ T cells responding to autologous EBV-transformed B cells infected with vaccinia virus-HIV recombinants (stacked-bar histograms), autologous primary CD4+ T cells infected with HIVSF162 (blue histograms), and autologous primary CD4+ T cells expressing high levels of autologous virus (gold histograms) for three B*57+ LTNPs and six B*57+ progressors are shown. p24+ CD3+ percentages are the percentages of CD4+ T cells infected with and expressing HIVSF162 or expressing autologous p24 in each experiment. These results are representative of at least three experiments.
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