Explosion of tuberculin-specific Th1-responses induces immune restoration syndrome in tuberculosis and HIV co-infected patients

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Abstract
To test the hypothesis that an acute exacerbation of mycobacteria-specific Th1 response after HIV infection control by HAART causes immune restoration syndrome (IRS) in HIV–tuberculosis (TB) coinfected patients. Prospective, multicenter study of 19 consecutive untreated HIV–TB coinfected patients included when initiating antimycobacterial 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 [purified protein derivative (PPD), ESAT-6, 85B] Th1 cells producing interferon (IFN)-γ quantified by ELISpot, in vitro production of 25 cytokines/chemokines in antigen-stimulated peripheral blood mononuclear cell (PBMC) supernatants quantified by chemiluminescence. Seven patients (37%) experienced IRS (IRS+). Mycobacteria-specific (PPD) Th1 IFN-γ-producing cells increased sharply during IRS (median, 2970 spot forming cells/106 PBMC), but not the cytomegalovirus-specific responses tested as control. Only three IRS+ patients had low ESAT-6− but no 85B-specific responses. 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 [interleukin (IL)-2, IL-12, IFN-γ, IP10 and monokine-induced by IFN-γ] without Th2 cytokines, and a peak of non-specific inflammatory cytokines/chemokines (TNF-α, IL-6, IL-1β, IL-10, RANTES and MCP-1) occurred. These findings were independent from CD4 cell count, viral loads or time of HAART initiation. An acute exacerbation of Th1 responses against mycobacterial antigens 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.