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. 2002 Sep;76(17):8690-701.
doi: 10.1128/jvi.76.17.8690-8701.2002.

Consistent patterns in the development and immunodominance of human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T-cell responses following acute HIV-1 infection

Xu G Yu  1 , Marylyn M Addo, Eric S Rosenberg, William R Rodriguez, Paul K Lee, Cecily A Fitzpatrick, Mary N Johnston, Daryld Strick, Philip J R Goulder, Bruce D Walker, Marcus Altfeld
Affiliations

Consistent patterns in the development and immunodominance of human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T-cell responses following acute HIV-1 infection

Xu G Yu et al. J Virol. 2002 Sep.

Abstract

Human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T-cell responses generated during acute infection play a critical role in the initial control of viremia. However, little is known about the viral T-cell epitopes targeted during acute infection or about their hierarchy in appearance and relative immunodominance over time. In this study, HIV-1-specific CD8+ T-cell responses in 18 acutely infected individuals expressing HLA-A3 and/or -B7 were characterized. Detailed analysis of CD8 responses in one such person who underwent treatment of acute infection followed by reexposure to HIV-1 through supervised treatment interruptions (STI) revealed recognition of only two cytotoxic T-lymphocyte (CTL) epitopes during symptomatic acute infection. HIV-1-specific CD8+ T-cell responses broadened significantly during subsequent exposure to the virus, ultimately targeting 27 distinct CTL epitopes, including 15 different CTL epitopes restricted by a single HLA class I allele (HLA-A3). The same few peptides were consistently targeted in an additional 17 persons expressing HLA-A3 and/or -B7 during acute infection. These studies demonstrate a consistent pattern in the development of epitope-specific responses restricted by a single HLA allele during acute HIV-1 infection, as well as persistence of the initial pattern of immunodominance during subsequent STI. In addition, they demonstrate that HIV-1-specific CD8+ T-cell responses can ultimately target a previously unexpected and unprecedented number of epitopes in a single infected individual, even though these are not detectable during the initial exposure to virus. These studies have important implications for vaccine design and evaluation.

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Figures

FIG. 1.
FIG. 1.
Viral loads (HIV-1 RNA copies per ml of plasma) in study subject AC-06 during the 34-month study period are shown on a logarithmic scale. Shading represents periods on HAART. The number of regions targeted by CD8+ T cells in AC-06 is given below the graph.
FIG. 2.
FIG. 2.
HIV-1-specific CD8+ T-cell responses to overlapping peptides in subject AC-06. The amino acid sequences and locations within HIV-1 proteins of all overlapping peptides targeted by virus-specific CD8+ T lymphocytes in subject AC-06 are shown. A total of 25 different regions within HIV-1 were targeted by CD8+ T cells.
FIG. 3.
FIG. 3.
Characterization of HLA-A3- and HLA-B7-restricted optimal HIV-1-specific CTL epitopes in subject AC-06. Graphs show the HLA class I restriction (left panels) and optimal amino acid sequences (right panels) of two novel HLA-A3-restricted CTL epitopes (A) and two novel HLA-B7-restricted CTL epitopes (B). HLA restriction was determined using peptides presented by autologous and partially HLA matched BCL in a 51Cr release assay. Solid bars, percent specific lysis of target cells pulsed with peptide; hatched bars, percent specific lysis of control target cells pulsed with no peptide. Fine mapping of the optimal epitope was done using serial dilutions of truncated peptides in an IFN-γ ELISPOT assay, and results are given as SFC per 106 PBMC.
FIG. 4.
FIG. 4.
Longitudinal evolution of the magnitude and breadth of HIV-1-specific CD8+ T-cell responses on the single-epitope level during treated acute infection and STI in subject AC-06. The magnitudes of CD8+ T-cell responses (given as SFC/106 PBMC) directed against the HIV-1 proteins Gag, Pol, and Env, as well as against the accessory HIV-1 proteins (Vif, Vpr, and Vpu) and the regulatory HIV-1 proteins (Rev and Tat), in subject AC-06 during the 34-month study period are shown. The number of CTL epitopes targeted within each HIV-1 protein or protein group is indicated above each bar. The periods on treatment (HAART) are indicated above the graph; the time after infection and the total number of CTL epitopes targeted at each time point are shown below the graph. Only two CTL epitopes, one in HIV-1 Gag and one in HIV-1 Env, were targeted during acute infection, but virus-specific CD8+ T-cell responses targeted a total of 27 different CTL epitopes at the end of the second STI.
FIG. 5.
FIG. 5.
Quantification of the contributions of HLA-A3-restricted and HLA-B7- or -Cw7-restricted CD8+ T-cell responses to total HIV-1-specific CD8+ T-cell responses in subject AC-06. PBMC of AC-06 were incubated with autologous BCL pulsed with either the HLA-B7-restricted immunodominant p24 Gag epitope GPGHKARVL (B), all 27 targeted optimal CTL epitopes (C), the 12 HLA-B7- or -Cw7-restricted optimal CTL epitopes (D), or the 15 HLA-A3-restricted optimal CTL epitopes (E) recognized by AC-06. BCL pulsed without peptide were used as negative controls (A). Percentages of peptide-specific IFN-γ-producing CD8+ T cells after subtraction of background activity are given in the individual plots.
FIG. 6.
FIG. 6.
Frequency of recognition of optimal CTL epitopes during acute HIV-1 infection and after STI. (A) Percentages of individuals expressing HLA-A3 (n = 14) who recognize the individual HLA-A3-restricted optimal CTL epitopes 1 to 15 during acute HIV-1 infection (solid bars) and after 12 months of treatment with HAART (hatched bars). (B) Percentages of individuals expressing HLA-A3 (n = 7) who recognize the individual HLA-A3-restricted optimal CTL epitopes 1 to 15 following STI. (C) Percentages of individuals expressing HLA-B7 (n = 11) who recognize the individual HLA-B7-restricted optimal CTL epitopes 1 to 15 during acute HIV-1 infection (solid bars) and after 12 months of treatment with HAART (hatched bars). (D) Percentages of individuals expressing HLA-B7 (n = 7) who recognize the individual HLA-B7-restricted optimal CTL epitopes 1 to 15 following STI. The amino acid sequences and corresponding HIV-1 proteins for the CTL epitopes tested are given at the bottom of the figure.
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