Association between discordant immunological response to highly active anti-retroviral therapy, regulatory T cell percentage, immune cell activation and very low-level viraemia in HIV-infected patients

Abstract

The mechanisms sustaining the absence of complete immune recovery in HIV-infected patients upon long-term effective highly active anti-retroviral therapy (HAART) remain elusive. Immune activation, regulatory T cells (T(regs)) or very low-level viraemia (VLLV) have been alternatively suspected, but rarely investigated simultaneously. We performed a cross-sectional study in HIV-infected aviraemic subjects (mean duration of HAART: 12 years) to concomitantly assess parameters associated independently with inadequate immunological response. Patients were classified as complete immunological responders (cIR, n = 48) and inadequate immunological responders (iIR, n = 39), depending on the CD4(+) T cell count (> or < 500/mm(3)). Clinical and virological data (including very low-level viraemia) were collected. In parallel, immunophenotyping of CD4(+) lymphocytes, including T(reg) subsets, and CD8(+) T cells was performed. Percentages of activated CD4(+) T cells, T(regs), effector T(regs) and terminal effector T(regs) were found to be significantly elevated in iIR. Neither the percentage of activated CD8(+) T cells nor VLLV were found to be associated with iIR. In the multivariate analysis, nadir of CD4(+) T cell count and percentage of T(regs) were the only two parameters associated independently with iIR [odds ratio (OR) = 2·339, P = 0·001, and OR = 0·803, P = 0·041]. We present here the largest study investigating simultaneously the immune response to long-term HAART, activation of CD4(+) and CD8(+) T cells, T(reg) percentages and very low-level viraemia. Causative interactions between T(regs) and CD4(+) T cells should now be explored prospectively in a large patients cohort.

Keywords: HAART; immune activation; immunological response; regulatory T cells; very low-level viraemia.

Figure 1

Regulatory T cell (T_reg) percentages. (a) T_reg percentages in inadequate immunological responder (iIR, n = 39) and complete immunological responder (cIR, n = 48) groups. (b) Association between T_reg percentages and CD4⁺ T cells for the 87 studied patients [*P < 0·05 Student's t-test and Spearman's correlation test for (a) and (b), respectively].

Figure 2

Correlations between CD4⁺ T cell absolute count and activated CD4⁺ T cells (CD4⁺human leucocyte antigen D-related (HLA-DR)⁺) (Spearman's correlation test, n = 87 patients).

Figure 3

Correlations between regulatory T cells (T_regs) and immune activation. (a) T_regs and activated CD4⁺ T cells (CD4⁺human leucocyte antigen D-related (HLA-DR)⁺). (b) T_regs and activated CD8⁺ T cells (CD8⁺CD38⁺) (Pearson's correlation test, n = 87 patients).