Clinical Outcome of HIV Viraemic Controllers and Noncontrollers with Normal CD4 Counts Is Exclusively Determined by Antigen-Specific CD8+ T-Cell-Mediated HIV Suppression

Abstract

In this cross-sectional study we evaluated T-cell responses using several assays to determine immune correlates of HIV control that distinguish untreated viraemic controllers (VC) from noncontrollers (NC) with similar CD4 counts. Samples were taken from 65 ART-naïve chronically HIV-infected VC and NC from Thailand with matching CD4 counts in the normal range (>450 cells/μl). We determined HIVp24-specific T-cell responses using standard Interferon-gamma (IFNγ) ELISpot assays, and compared the functional quality of HIVp24-specific CD8+ T-cell responses using polychromatic flow cytometry. Finally, in vitro HIV suppression assays were performed to evaluate directly the activity of CD8+ T cells in HIV control. Autologous CD4+ T cells were infected with primary patient-derived HIV isolates and the HIV suppressive activity of CD8+ T cells was determined after co-culture, measuring production of HIVp24 Ag by ELISA. The HIVp24-specific T-cell responses of VC and NC could not completely be differentiated through measurement of IFNγ-producing cells using ELISpot assays, nor by the absolute cell numbers of polyfunctional HIVp24-specific CD8+ T cells. However, in vitro HIV suppression assays showed clear differences between VC and NC. HIV suppressive activity, mediated by either ex vivo unstimulated CD8+ T cells or HIVp24-specific T-cell lines, was significantly greater using cells from VC than NC cells. Additionally, we were able to demonstrate a significant correlation between the level of HIV suppressive activity mediated by ex vivo unstimulated CD8+ T cells and plasma viral load (pVL) (Spearman r = -0.7345, p = 0.0003). This study provides evidence that in vitro HIV suppression assays are the most informative in the functional evaluation of CD8+ T-cell responses and can distinguish between VC and NC.

Prime-Boost Immunization Eliminates Metastatic Colorectal Cancer by Producing High-Avidity Effector CD8+ T Cells

“…Indeed, analysis of untreated patients with poor HIV control (progressors) and those with HIV control (nonprogressors) demonstrated that nonprogressors possessed higher functionality than progressors (39). More recently, suppression of HIV replication, through killing of HIV-infected targets by high avidity CD8 + T cells (40) was found to be the exclusive determinant of HIV viremic control in progressors (41), suggesting that CD8 + T cell avidity, rather than polyfunctionality, may also underlie HIV control. Similarly, experimental manipulation of TCR avidity employing adoptive transfer of T cells genetically engineered to express TCRs of varying affinities to the melanoma antigen gp100 demonstrated that antitumor efficacy was determined by TCR affinity (33).…”

Preservation of Lymphopoietic Potential and Virus Suppressive Capacity by CD8+ T Cells in HIV-2–Infected Controllers

“…This capacity was not found in cART-treated or untreated viremic HIV-1 patients, either during the acute or chronic phase of infection (38)(39)(40)(41). HIV-1 suppression assays provide the most robust method to distinguish between the functional capacities of CD8 + T cells from HIV-1 controllers and noncontrollers (40,42,43). We thus sought to adapt this in vitro assay to the study of HIV-2 using an SBL virus strain (20), with supernatant p27 concentration as a readout.…”

Optimal maturation of the SIV-specific CD8+T-cell response after primary infection is associated with natural control of SIV. ANRS SIC study

“…CD8 + T-cells from HICs typically suppress ex vivo infection of autologous CD4 + T-cells (Angin et al, 2016; Buckheit et al, 2012; Julg et al, 2010; Saez-Cirion et al, 2007; Saez-Cirion et al, 2009; Tansiri et al, 2015). We therefore investigated this property as a potential discriminant between SICs and VIRs.…”

“…The capacity of CD8 + T-cells to suppress infection of autologous CD4 + T-cells directly ex vivo is a particular feature of HICs (Almeida et al, 2009; Angin et al, 2016; Buckheit et al, 2012; Julg et al, 2010; Saez-Cirion et al, 2007; Saez-Cirion et al, 2009; Tansiri et al, 2015) that is mediated by the rapid elimination of infected CD4+ T-cells (Saez-Cirion et al, 2007). Irrespective of subsequent outcome, we detected relatively weak CD8 + T-cell-mediated SIV-suppressive activity during primary infection, despite the vigorous mobilization of SIV-specific CD8 + T-cells.…”

“…These observations suggest that naturally generated HIV/SIV-specific CD8 + T-cells are frequently suboptimal in terms of antiviral efficacy, potentially reflecting limited cross-reactivity and/or intrinsic defects in the arsenal of effector functions required to eliminate infected CD4 + T-cells (Du et al, 2016; Lecuroux et al, 2013). The latter possibility is especially intriguing in light of ex vivo experiments showing that effective suppression of viral replication is a particular feature of CD8 + T-cells isolated from HIV controllers (HICs) (Angin et al, 2016; Saez-Cirion et al, 2007; Saez-Cirion et al, 2009; Tansiri et al, 2015).…”