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

Summary 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 CD 4 + T cell count (> or < 500/mm 3 ). Clinical and virological data (including very low‐level viraemia) were collected. In parallel, immunophenotyping of CD 4 + lymphocytes, including T reg subsets, and CD 8 + T cells was performed. Percentages of activated CD 4 + 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 CD 8 + T cells nor VLLV were found to be associated with iIR . In the multivariate analysis, nadir of CD 4 + 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 CD 4 + and CD 8 + T cells, T reg percentages and very low‐level viraemia. Causative interactions between T regs and CD 4 + T cells should now be explored prospectively in a large patients cohort.