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

SummaryThe 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 (Tregs) 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 Treg subsets, and CD8 + T cells was performed. Percentages of activated CD4 + T cells, Tregs, effector Tregs and terminal effector Tregs 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 Tregs 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, Treg percentages and very low-level viraemia. Causative interactions between Tregs and CD4 + T cells should now be explored prospectively in a large patients cohort.

Increased Regulatory T-Cell Percentage Contributes to Poor CD4+ Lymphocytes Recovery: A 2-Year Prospective Study After Introduction of Antiretroviral Therapy

“…In this context, CD4 nadir is known as an important prognostic factor of CD4 count reconstitution [17, 20]. Here, we extend these results by describing, in a prospective cohort study, that Treg percentage, as CD4 nadir, was as an independent predictor of low CD4 recovery despite virological success.…”

Incomplete immune reconstitution in HIV/AIDS patients on antiretroviral therapy: Challenges of immunological non-responders

“…a Total CD4 + T-cell count > 500 cells/µl at 2-12 years after ART initiation, with an undetectable plasma VL. 16,179,[230][231][232][233] Increase in the CD4 + T-cell count < 200 cells/µl from baseline at 7 years after ART initiation, with plasma HIV RNA < 200 copies/ml.…”

Residual inflammation and viral reservoirs

“…The suppressive capacity of Tregs is influenced by several factors, such as IL-2, inhibitory cytokines (IL-10, TGF-β, or IL-35) and ICs such as CTLA-4 and LAG-3 [84, 85]. In lymphopenic ART individuals, the frequency of Tregs is associated with markers of activation [86] and Tregs may act as a preferential reservoir for HIV during ART [87]. …”