Objective: In vitro peripheral blood mononuclear cells (PBMCs) of HIV-infected subjects show defective immune responses including impaired proliferative responses after stimulation with antigens and mitogens. The cytokine interferon-gamma, which seems to play an important role in HIV infection, induces neopterin formation and in parallel also tryptophan degradation by the enzyme indoleamine 2,3-dioxygenase.
Design: : In this study, interferon-gamma-mediated pathways were examined in the plasma of patients and evaluated for associations with the proliferative responses of PBMC to mitogens in vitro.
Methods: To assess the actual status of immune system activation in patients, plasma concentrations of interferon-gamma, neopterin, tryptophan, and kynurenine were measured by enzyme-linked immunosorbent assay or by high-performance liquid chromatography; the ratio of kynurenine to tryptophan was calculated. Viral load, CD4 counts, and the in vivo immune activation status were compared with the in vitro responses of PBMC isolated from the same patients. PBMCs were stimulated with the mitogens concanavalin A, phytohemagglutinin, and pokeweed mitogen, and their proliferation was assessed by H-thymidine incorporation.
Results: The in vitro proliferative capacity of PBMC was associated with viral load, CD4 counts, and also tryptophan degradation. Particularly, high neopterin concentrations were observed to be the best predictor of impaired proliferative response in logistic regression analysis.
Conclusions: The higher the degree of immune activation in vivo, the lower is the proliferative capacity of PBMC in vitro.