Abstract
HIV replication is only partially controlled by HIV-specific activated effector T cells in chronic HIV infection and strategies are warranted to improve their efficacy. Chronic T cell activation is generally accompanied by regulation of antigen-specific T cell responses which may impair an effective control of chronic infections. The impact of HIV-induced T cell regulation on individual patients’ disease progression is largely unknown, since classical T cell activation assays reflect net activation with regulation as unknown contributing factor. We here explore a quantitative parameter for antigen-induced cytokine-mediated regulation (RAC) of HIV-specific effector T cell activation by functional antibody-blockade of IL-10 and transforming growth factor-β. HIV Env- and Gag-specific T cell activation and RAC were estimated in peripheral blood mononuclear cells from 30 treatment-naïve asymptomatic HIV-infected progressors (CD4 count 472/µl, HIV RNA 37500 copies/ml) stimulated with overlapping peptide panels for 6 days. RAC was estimated from differences in T cell activation between normal and blocked cultures, and related to annual CD4 loss, immune activation (CD38) and microbial translocation (plasma lipopolysaccharides). RAC was heterogeneously distributed between individual patients and the two HIV antigens. Notably, RAC did not correlate to corresponding classical activation. Env RAC correlated with CD38 and CD4 loss rates (r> = 0.37, p = <0.046) whereas classical Gag activation tended to correlate with HIV RNA (r = −0.35, p = 0.06). 14 patients (47%) with low RAC’s to both Env and Gag had higher CD8 counts (p = 0.014) and trends towards lower annual CD4 loss (p = 0.056) and later start with antiretroviral treatment (p = 0.07) than the others. In contrast, patients with high RAC to both Env and Gag (n = 8) had higher annual CD4 loss (p = 0.034) and lower CD8 counts (p = 0.014). RAC to Env and Gag was not predicted by classical activation parameters and may thus provide additional information on HIV-specific immunity. RAC and other assessments of regulation deserve further in-depth exploration.
Highlights
Chronic human immunodeficiency virus type 1 (HIV) infection leads to a variable but progressive loss of immune functions in most patients
The progression rate is mainly influenced by two opposing factors, namely HIV-associated chronic immune activation [1,2,3] and the efficacy of HIV-specific T cell responses [4,5]
The patients represented a spectre of HIV-associated immune activation determined by CD38 densities on total CD8+ and CD8+programmed death-1 (PD-1)+ T cells [8] and were chosen from a larger cross-sectional prospective study on immunological factors in HIV
Summary
Chronic human immunodeficiency virus type 1 (HIV) infection leads to a variable but progressive loss of immune functions in most patients. Regulation of effector T cells protects the host from damage in chronic infection, but may impair effective immune control It is mediated by a number of mechanisms, including the expression of inhibitory receptors in the immune synapse such as CTLA-4 [18] and programmed death-1 (PD-1) [19,20], or via soluble inhibitory cytokines, IL10 and transforming growth factor-b (TGF-ß). These two key inhibitory cytokines impede pro-inflammatory responses by T cells, natural killer cells, monocytes and macrophages and are secreted by a number of cell types including Treg [21,22,23,24]
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