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

ABSTRACT

OBJECTIVES: 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. DESIGN: 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. METHODS: Mycobacteria-specific [purified protein derivative (PPD), ESAT-6, 85B] Th1 cells producing interferon (IFN)-gamma quantified by ELISpot, in vitro production of 25 cytokines/chemokines in antigen-stimulated peripheral blood mononuclear cell (PBMC) supernatants quantified by chemiluminescence. RESULTS: Seven patients (37%) experienced IRS (IRS+). Mycobacteria-specific (PPD) Th1 IFN-gamma-producing cells increased sharply during IRS (median, 2970 spot forming cells/10 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-gamma, IP10 and monokine-induced by IFN-gamma] without Th2 cytokines, and a peak of non-specific inflammatory cytokines/chemokines (TNF-alpha, IL-6, IL-1beta, IL-10, RANTES and MCP-1) occurred. These findings were independent from CD4 cell count, viral loads or time of HAART initiation. CONCLUSION: 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.