Background:  IL 2 treatment of HIV-infection has shown efficacy in some patients in the ESPRIT trial, but no biomarkers identify patients who profit from this expensive treatment, that has many side effects. Gas is one of the most important proteins in cellular signal transduction. It mediates the receptor-stimulated intracellular cAMP rise through activation of the adenylate cyclase. Depending on cell type this rise in cAMP induces an increase in heart rate, lipolysis, or apoptosis. A novel single nucleotide polymorphism (SNP) was identified in regulatory regions of GNAS, which alter transcription and, thereby, expression of Gas. GNAS polymorphisms could be a prognostic factor of treatment success with HAART or interleukin-2 (IL-2).

Methods:  In the first trial, consecutively recruited patients treated with HAART were genotyped. The endpoint of the study was the change in viral load in the different groups (AA/AG/GG). In the second study, 75 German participants of the ESPRIT trial were genotyped. The changes of the CD4 count under therapy were observed in the 3 groups.

Results:  Viral load of patients with GG genotype was significantly lower 8 weeks after initiating HAART and at the end of the study than in people with AA or AG genotype. On the other hand, patients with GG genotype showed little or no response to IL-2 treatment, while patients with AG or AA genotype showed significantly higher CD4 counts after IL-2 administration. GNAS polymorphisms had no significant effect on CD4 counts in the placebo group.

Conclusions:  These data suggest that IL-2-induced CD4 rises are genetically determined and that genotyping the GNAS G(-1211)A polymorphism could identify treatment responders.This finding could be of utmost clinical significance.