Gag-Specific CD8 T-Cell Proliferation Is Associated With Higher Peripheral Blood Levels of Transforming Growth Factor-β and Gut-Homing T Cells in Youths Perinatally Infected With Human Immunodeficiency Virus-1: The ANRS-EP38-IMMIP Study

Abstract

Background: Gag-specific T lymphocytes play a key role in the control of human immunodeficiency virus (HIV) replication. Their restoration will be important for future reservoir targeting strategies. In this study, we aimed to identify immune correlates of Gag-specific CD8 T-cell proliferation in youths with perinatally acquired HIV-1 infection.

Methods: The ANRS-EP38-IMMIP study included youths of 15 to 24 years of age. Fifty-three were taking combination anti-retroviral therapy and aviremic at the time of the study and had undergone valid 5-6-carboxyfluorescein diacetate succimidyl ester-based flow cytometry T-cell proliferation assays. Plasma analytes were quantified by enzyme-linked immunosorbent assay or multiplex assays. Peripheral blood cells were phenotyped by flow cytometry. Logistic regression was used to study the association between Gag-specific T-cell proliferation and immune markers.

Results: Patients with Gag-specific CD8 T-cell proliferation had higher levels of plasma transforming growth factor (TGF)-β1, a lower proportion of naive cells among regulatory T cells (Tregs), and higher percentages of CD4 and CD8 T cells expressing the α₄β₇ integrin or CD161 molecule than those without a Gag-specific response. These associations were significant based on analyses including potential confounders.

Conclusions: Preserved Gag-specific CD8 T-cell proliferation was associated with higher TGF-β1 levels and increased percentages of T cells with a gut-homing phenotype at least 15 years after HIV infection during the perinatal period.

Keywords: CD8 T cells; HIV; mucosal immunity; perinatal infection; regulatory T cells..

Figure 1.

Gag-specific CD8 T-cell proliferation and plasma levels of cytokines. The levels of immune parameters are presented as a function of Gag-specific CD8 T-cell proliferation. Open and closed symbols represent CD8 non-responders (CD8NRs) and CD8 responders (CD8Rs) in the Gag-specific T-cell proliferation assay. Lines represent median values. A: plasma IL-12p70 (pg/mL), B: plasma IL-18 (pg/mL), C: plasma IL-10 (pg/mL), D: plasma TGF-β1 (ng/mL), E: plasma IL-1β (pg/mL), F: plasma IL-6 (pg/mL), G: plasma IL-17 (pg/mL), and H: plasma IL-23 (pg/mL).

Figure 2.

Gag-specific CD8 T-cell proliferation and T cell subsets. Data are presented as described in Figure 1. A: percentages of CD4 Tregs among total CD4 cells, B: percentages of naive cells among CD4 Tregs, C: percentages of central memory cells among CD4 Tregs, D: percentages of effector memory cells among CD4 Tregs, E: percentages of CD161+ CD4 T-cells among total CD4 T cells, F: percentages of CD161+ CD8αα T-cells among total CD8 T cells, G: percentages of α4+β7+ memory CD4 T-cells among total CD4 T cells, H: percentages of α4+β7+ memory CD8 T-cells among total CD8 T cells, I: percentages of HLA-DR+CD38+ cells among memory CD8 T cells, J: percentages of CD279+ cells among memory CD8 T cells, K: percentages of CD57+ T-cells among CD28- effector memory (CD45RA-CD197−) CD8 T cells, L: percentages of CD57+ T-cells among CD28- effector (CD45RA+CD197−) CD8 T cells.

Figure 3.

Logistic regression analysis of the association between Gag-specific CD8 T-cell proliferation and immune parameters. Results from univariate and multivariate logistic regression are presented as ORs and 95% confidence intervals. P values are indicated and black symbols correspond to P values < .05. Multivariate analysis included ethnicity and the duration of plasma HIV RNA suppression as covariables. The ORs are given per 100 pg/mL of IL-18, per ng of TGF-β1, per 10 pg/mL of IL-1β, and per 1% of each T-cell subset.