Selective depletion of high-avidity human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T cells after early HIV-1 infection

Abstract

Human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T cells in early infection are associated with the dramatic decline of peak viremia, whereas their antiviral activity in chronic infection is less apparent. The functional properties accounting for the antiviral activity of HIV-1-specific CD8+ T cells during early infection are unclear. Using cytokine secretion and tetramer decay assays, we demonstrated in intraindividual comparisons that the functional avidity of HIV-1-specific CD8+ T cells was consistently higher in early infection than in chronic infection in the presence of high-level viral replication. This change of HIV-1-specific CD8+ T-cell avidity between early and chronic infections was linked to a substantial switch in the clonotypic composition of epitope-specific CD8+ T cells, resulting from the preferential loss of high-avidity CD8+ T-cell clones. In contrast, the maintenance of the initially recruited clonotypic pattern of HIV-1-specific CD8+ T cells was associated with low-level set point HIV-1 viremia. These data suggest that high-avidity HIV-1-specific CD8+ T-cell clones are recruited during early infection but are subsequently lost in the presence of persistent high-level viral replication.

Figures

FIG. 1.

Lower total magnitude of cytokine-secreting and degranulating HIV-1-specific CD8+ T cells during early HIV-1 infection than during chronic infection. Data reflect the total magnitude of CD8+ T cells secreting IFN-γ, TNF-α, or MIP-1β or expressing CD107a/b on the cell surface following stimulation with overlapping peptides corresponding to the entire HIV-1 proteome in individuals with early (n = 10) and chronic (n = 10) HIV-1 infection. Results are presented as box-whisker plots, indicating the median and the 10th, 25th, 75th, and 90th percentiles.

FIG. 2.

Higher functional avidity of HIV-1-specific CD8+ T cells in early infection than in chronic HIV-1 infection. (A) Dot plots reflecting the proportion of IFN-γ-secreting CD8+ T cells following stimulation with the HIV-1 epitopic peptide B8-FL8 in serial 10-fold dilutions in study individual AC-15 during early and chronic infections. Percentages indicate the proportions of gated CD8+ IFN-γ-positive lymphocytes. (B to D) Intraindividual analysis of the functional avidities of IFN-γ-secreting HIV-1-specific CD8+ T cells recognizing the same viral epitope in early and chronic infections. Dose-response curves indicate the proportions of CD8+ T cells secreting IFN-γ, following peptide stimulation in serial 10-fold dilutions. Data were normalized (maximum = 1). Dashed lines and triangles correspond to chronic infection; solid lines and squares reflect data obtained during early infection. (B) Data from individuals started on antiretroviral therapy during early infection and subsequently undergoing STIs. (C and D) Data from study persons who remained completely untreated after early infection in the presence of high-level (C) or low-level (D) viremia. (E) Epitopic peptide concentrations eliciting 50% of the maximum of the indicated functional activity (EC50) in the 10 study individuals during early and chronic infections. Antigen-specific TNF-α secretion was below the threshold of detection by flow cytometry for five study individuals.

FIG. 3.

Slower tetramer dissociation of HIV-1-specific CD8+ T cells in early infection than in chronic infection. Tetramer dissociation curves of HIV-1-specific CD8+ T cells in early (squares) and chronic (triangles) HIV-1 infection in study persons treated during early infection and subsequently undergoing STIs (A) or remaining completely untreated after early infection in the presence of high-level (B) or low-level (C) viremia. (D) Koff of HIV-1-specific CD8+ T cells during early and chronic infections in the 10 study persons described in the text.

FIG. 4.

Clonotypic compositions of HIV-1-specific CD8+ T-cell populations during early and chronic HIV-1 infections (A) in individuals with STIs and (B and C) in five study persons who remained treatment naïve after early infection in the presence of high-level (B) or low-level (C) viremia. Each fraction corresponds to one Vβ clonotype detected by TCR sequencing. Clonotypes shown in black or gray were detected during both early and chronic infection, while clonotypes shown in white were detected exclusively during early or chronic infection.

FIG. 5.

Tetramer dissociation and phenotypic characteristics of HIV-1-specific CD8+ T-cell clonotypes persisting or disappearing after early HIV-1 infection. (A) Dot plots indicating the proportions of tetramer-positive CD8+ T cells with specific TCR Vβ chain usage during early infection in the three indicated study persons. Gating was performed according to forward scatter/side scatter characteristics of the lymphocyte population and CD8 expression. (B) Intraindividual comparison of tetramer dissociation rates of HIV-1-specific CD8+ T-cell clonotypes persisting or disappearing after early infection. (C) Histograms (presented on a log scale) indicating the expression of CD127, CD38, and Ki-67 during early HIV-1 infection in HIV-1-specific clonotypes persisting or disappearing after early infection. Dotted lines correspond to HIV-1-specific CD8+ T-cell clones eliminated after early infection, and solid lines correspond to CD8+ T-cell clones persisting after acute HIV-1 infection. Scattered lines indicated background staining intensity (no antibodies). In study subject AC-46, B8-FL8-specific CD8+ T cells were analyzed using Vβ9 (6.5% of all clonotypes in early infection and 0% of clonotypes in chronic infection) and compared to those analyzed using Vβ20.1 (25% of all clonotypes in early infection and 31.6% of clonotypes in chronic infection). In study individual AC-09, A2-IV9-specific CD8+ T-cell clonotypes were analyzed using Vβ20.1 (38% of clonotypes in early infection and 0% of clonotypes in chronic infection) and compared to those analyzed using Vβ10.3 (7.6% of clonotypes in early infection and 62% in chronic infection). In study person AC-14, we analyzed the B8-FL8-specific clonotypes using Vβ27 (42.5% of all clonotypes in early infection and 0% in chronic infection) or Vβ28 (7.9% of all clonotypes in early infection and 5.8% in chronic infection) (Table 3). MFI, mean fluorescence intensity.