Role ofIn VitroStimulation with Lipopolysaccharide on T-Cell Activation in HIV-Infected Antiretroviral-Treated Patients

Abstract

We investigated the effect of LPS in vitro stimulation on T-cell activation in HIV-infected patients with different CD4+ recovery on HAART. PBMCs from 30 HIV-positive, HAART-treated, aviremic individuals with different CD4+ reconstitution (Low Responders: CD4+ < 350/μL; Intermediate Responders: CD4+ 350–599/μL; High Responders: CD4+ ≥ 600/μL) were cultured with LPS and the proportion of HLA-DR/CD38- and Ki67-expressing CD4+/CD8+ T-cells was measured (flow cytometry). Upon LPS stimulation, significantly higher CD4+ and CD8+HLA-DR+ cells were shown in LR and IR versus HIV-negative controls. While no differences in the proportion of LPS-stimulated CD4+CD38+ cells were recorded amongst HIV-positive subgroups, CD8+CD38+ cells were more elevated in patients with lower CD4+ recovery on HAART (i.e., LR and IR). Upon in vitro LPS stimulation, HLA-DR and CD38 expression on T-cells are differentially regulated. While HLA-DR induction reflects impaired CD4+ reconstitution on HAART, cell-surface CD38 expression is increased only on CD8+ T-cells, allowing to speculate that the sole induction of CD38 on CD4+ cells may not be sufficient to depict LPS-driven immune activation in HIV.

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS

“…In that study, in vitro exposure to microbial TLR ligands promoted the cell surface expression of lymphocyte-homing and activation/apoptosis molecules on CD4 ϩ and CD8 ϩ T cells (67). Consistent with those observations, in vitro stimulation by microbial and viral TLR ligands was shown to induce T-cell activation in both antiretroviral-naïve and ART-treated, HIV-infected patients (68,69). By extension, those in vitro findings suggested that systemic exposure to TLR ligands in HIV-infected patients results in heightened immune activation, effector T-cell sequestration in lymphoid tissues, and T-cell turnover, thus reinforcing the hypothesis that microbial translocation is a crucial determinant of immune activation.…”

Relationship between T-cell HLA-DR expression and intravenous immunoglobulin treatment response in Kawasaki disease

“…T-cell activation (16)(17)(18), and have previously shown that its expression is low in CD4 + and CD8 + T cells during the acute phase of KD (20,28,29). This data was further corroborated by another research group, which observed that the number of HLA-DR + CD8 + T cells does not increase during the acute phase of KD (30).…”

“…Autopsy studies of children with KD who died during the acute phase clearly indicate that CD4 + and CD8 + T cells participate in the transmural infiltration of the coronary arterial wall (14). Notably, human leukocyte antigen-DR (HLA-DR), a cell-surface glycoprotein encoded by the HLA-DR region of the major histocompatibility complex (15), is a known marker of T-cell activation (16)(17)(18), but the function of this antigen on the different T-cell populations during KD is unknown. In this study, we have investigated the relationship between HLA-DR expression on peripheral CD4 + and CD8 + T cells, and thus the activation of these cells, and the response to IVIG treatment in children with KD.…”

Stimulation of PBMC and Monocyte-Derived Macrophages via Toll-Like Receptor Activates Innate Immune Pathways in HIV-Infected Patients on Virally Suppressive Combination Antiretroviral Therapy

“…Along the same line, in vitro research has shown a direct link between microbial stimulation and immune activation in both HIV-uninfected (12, 37–39, 53) and HIV-infected untreated individuals through TLR signaling (18, 31, 33, 50, 59–61). …”

“…Besides, recent literature in both HIV-negative and HIV-positive individuals provided ex vivo evidence for a direct role of translocating microbial products in driving immune activation. In particular, ex vivo stimulation of PBMCs and antigen-presenting cells with bacterial ligands (including LPS), commensal bacteria, and combined bacterial and viral stimulus results in the production of pro- and anti-inflammatory cytokines (36–50). In cART-treated patients, increased CD8+ CD38+ cells have been reported upon LPS exposure in subjects with poor CD4+ T-cell restoration (50) as well as impaired IFN-α production, following stimulation of plasmacytoid dendritic cells with TLR7 and TLR9 agonists (51).…”