Background:  Simultaneous ART and anti-mycobacterial treatment in patients co-infected with HIV and tuberculosis (TB) frequently cause immune reconstitution syndrome (IRS). To test the hypothesis that an acute exacerbation of mycobacteria-specific Th1 response after HIV infection control by HAART causes IRS, we prospectively analyzed the kinetics of TB-specific Th1 immune response in TB/HIV-co-infected patients receiving anti-TB, then anti-HIV, therapy.

Methods:  Prospective, multicenter study of 22 consecutive untreated HIV/TB-co-infected patients included when initiating anti-mycobacterial therapy and sequentially evaluated during HAART and at time of IRS. IRS was defined according to classical clinical diagnostic criteria. Patients were declared IRS^­ if no IRS occurred within 3 months after HAART initiation. Mycobacteria-specific (tuberculin/PPD, ESAT-6, 85B) Th1 interferon-gamma (IFN-g)-producing cells were quantified by ELISpot, intracellular cytokine analysis (ICS) and in vitro production of 25 cytokines/chemokines in antigen-stimulated peripheral blood mononuclear cells (PBMC) supernatant quantified by chemiluminescence. Comparisons between groups were made using non-parametric Fischer exact and Mann-Whitney tests.

Results:  Within a median of 40 days after HAART onset (M₀), 9 patients (41%) experienced IRS (IRS⁺). M₀ median CD4 counts were 35/mm³ for IRS⁺ vs 56/mm³ for IRS­ (p = 0.09) and rose at M₃ by 101/mm³ vs 53/mm³ in IRS⁺/IRS^­ patients (p = 0.1). PPD-specific Th1 IFN-g-producing CD4 cells increased sharply during IRS from a baseline median of 56 up to 3409 SFC/10⁶ PBMC, but not cytomegalovirus (CMV)-specific responses tested as control. Those PPD-specific cells represented as much as 22% of CD4 cells by ICS, and all expressed activation marker (HLA-DR). Only 3 IRS⁺ patients had ESAT-6- but no 85B-specific responses at time of IRS. IRS^­ patients did not develop acute PPD-specific responses except in one case. In addition, at time of IRS a peak of PPD-specific Th1 cytokines/chemokines (IL-2, IL-12, IFN-γ, IP10, and MIG) without Th2 cytokines (IL-4, IL-5, IL-13, IL-15), and a peak of non-specific inflammatory cytokines/chemokines (TNF-a, IL-6, IL-1b, IL-10, RANTES, and MCP-1) occurred.

Conclusions:  Immune restoration concomitant to CD4 T-cell exposure to mycobacterial antigens contained in tuberculin but not in living TB pathogens appears to cause IRS in patients co-infected with HIV and TB. This key event provides new evidence valuable for the diagnosis and treatment of IRS.