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. 2002 Mar;76(5):2298-305.
doi: 10.1128/jvi.76.5.2298-2305.2002.

Magnitude of functional CD8+ T-cell responses to the gag protein of human immunodeficiency virus type 1 correlates inversely with viral load in plasma

Bradley H Edwards  1 , Anju Bansal, Steffanie Sabbaj, Janna Bakari, Mark J Mulligan, Paul A Goepfert
Affiliations

Magnitude of functional CD8+ T-cell responses to the gag protein of human immunodeficiency virus type 1 correlates inversely with viral load in plasma

Bradley H Edwards et al. J Virol. 2002 Mar.

Abstract

The importance of CD8+ T-cell responses in the control of human immunodeficiency virus type 1 (HIV-1) infection has been demonstrated, yet few studies have been able to correlate these responses with markers of HIV-1 disease progression. This study measured cell-mediated immune responses using peripheral blood mononuclear cells (PBMC) obtained from 27 patients with chronic HIV-1 infection, the majority of whom were off antiretroviral therapy. The ELISPOT assay was used to detect gamma interferon-secreting PBMC after stimulation with overlapping HIV-1 peptides spanning the Gag, Pol, Env, and Nef proteins in addition to the baculovirus-derived p24 and gp160 proteins. All volunteers had responses to at least one HIV-1-specific peptide. All but one of the subjects (96%) responded to the Gag peptide pool, and 86% responded to the Pol and/or Nef peptide pools. The magnitude and the breadth of T-cell responses directed to either the Gag or p24 peptide pools correlated inversely with viral load in plasma (r = -0.60, P < 0.001 and r = -0.52, P < 0.005, respectively) and directly with absolute CD4+ T-cell counts (r = 0.54, P < 0.01 and r = 0.39, P < 0.05, respectively) using the Spearman rank correlation test. Responses to the Pol and integrase peptide pools also correlated with absolute CD4+ T-cell counts (r = 0.45, P < 0.05 and r = 0.49, P < 0.01, respectively). No correlation with markers of disease progression was seen with specific T-cell responses directed toward the Env or Nef peptides. These data serve as strong evidence that major histocompatibility complex class I presentation of Gag peptides is an essential feature for any HIV-1 vaccine designed to elicit optimal CD8+ T-cell responses.

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Figures

FIG. 1.
FIG. 1.
HIV-1-specific immune responses as measured by the IFN-γ ELISPOT assay. (A) Responses to Gag, Pol, Env, and Nef by measuring IFN-γ secretion using PBMC stimulated with overlapping 20-mer peptide pools are represented for each individual subject. (B) HIV-1-specific responses using the 20-mer peptides that correspond to the listed proteins are demonstrated for each subject. The black bar represents the median response among the cohort for each of the protein responses. The AA adjusted score is defined as the magnitude of responses (median SFU/106 PBMC) divided by the number of AA in the respective protein sequences. The 20-mer peptide pools exactly represent the Gag, Pol, Env, and Nef proteins. The 20-mer peptide pools represent the smaller proteins as follows. Gag: matrix protein p17 (AA 1 to 110), capsid protein p24 (AA 140 to 361), nucleocapsid protein NC (AA 399 to 500); Pol: protease Pr (AA 57 to 155), reverse transcriptase RT (AA 155 to 593), RNase H (AA 601 to 710), and integrase IN (AA 711 to 1003); Env: surface protein gp120 (AA 1 to 431) and transmembrane protein gp41 (AA 513 to 856). ∗, FOJA3818 had measurements performed at two separate time points.
FIG. 2.
FIG. 2.
HIV-1-specific immune responses correlate with vRNA and absolute CD4+ T-cell counts. HIV-1-specific immune responses as measured by the 20-mer IFN-γ ELISPOT assay were compared with either vRNA (A) or absolute CD4+ T-cell counts (B) using linear regression analysis. The P values are shown for the slope of each data set.
FIG. 3.
FIG. 3.
IFN-γ secretion of PBMC stimulated with Gag peptides is due primarily to CD8+ T cells. The number of cells secreting IFN-γ was measured after unfractionated, CD8-depleted or CD4-depleted PBMC obtained from four subjects were stimulated with the Gag peptide pool overnight in an ELISPOT plate. For subject FRRA4172, the different cell subsets were also stimulated with peptides in the p24 protein (Bg and Cg) in addition to the optimized CD8+ T-cell peptides TL9 (TPQDLNTML) and KK10 (KRWIILGLNK), restricted by his HLA-B42 and B27 HLA class I proteins, respectively.
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