Short communication: enhanced CD8+ T cell apoptosis in HIV-infected adolescents with virologic failure on protease inhibitor-based therapy

Abstract

In this study, we investigated the possibility of differential effects of protease inhibitor (PI)-containing (PI(+)) and PI-sparing (PI(-)) antiretroviral therapies (ART) on CD8(+) T cell apoptosis. We retrospectively analyzed both PD-1 expression and CD8(+) T cell apoptosis in a cross-sectional study of HIV-positive adolescents and young adults (mean age = 17.4 years), with perinatally or behaviorally acquired HIV infection. Fifty-one specimens of cryopreserved peripheral blood mononuclear cells (PBMCs) were analyzed using 7-color flow cytometry: 20 from patients receiving PI(+) ART, 14 from PI(-) ART, and 17 from the untreated. The results showed that percentages of PD-1(+) CD8(+) T cells were strongly correlated with plasma viral loads regardless of treatment (p = 0.0001). The percentage of PD-1(+) CD8(+) T cells was also positively associated with percentages of Annexin V(+) CD8(+) T cells (p = 0.04) in the PI(+)-treated group. The fraction of apoptotic (Annexin V(+)) CD8(+) T cells was associated with viral load in the patients receiving ART that contained one or more protease inhibitors (p = 0.029), but not in the PI(-) or untreated groups. In summary, we found a direct correlation between PD-1 expression on CD8(+) T cells and HIV levels that was not affected by types of medications used in the ART of those adolescents, suggesting that virological success is necessary for PD-1 downregulation. CD8(+) T cell apoptosis was linked to high levels of PD-1 expression and HIV viremia. However, there was a higher degree of apoptosis among viremic patients receiving PI therapy, suggesting an immunologically adverse effect of continuing PI(+) therapy after virological failure.

FIG. 1.

Correlations of percentages of PD-1⁺ CD8⁺ T cells and percentages of Annexin V⁺ CD8⁺ T cells with patients' viral loads in different treatment groups. (A) Gating scheme of flow cytometric analysis of CD8⁺ T cells in PBMCs. Also, PD-1 expression and Annexin V staining in gated CD8⁺ T cells in Patient 1 (HIV VL = 27,333 copies/ml) and in Patient 2 (HIV VL <50 copies/ml) are shown in comparison. (B) Percentages of PD-1⁺ CD8⁺ T cells were positively associated with patients' viral loads, showing no treatment effect on the correlation. (C) Percentages of Annexin V⁺ CD8⁺ T cells were positively associated with viral loads in the PI⁺ ART group but not in the PI⁻ ART and no treatment groups. Gray triangles represent data of untreated patients. Black circles and open squares represent data of patients in the PI⁻ ART group and the PI⁺ ART group, respectively. Trendlines for all three subgroups are also shown. Viral load values are plotted as the actual value, or the limit of detection on the assay, if HIV RNA was not detected.