Background:  HIV-infected patients co-infected with HCV have modest responses to anti-HCV therapy relative HIV-uninfected individuals. The purpose of the study is to examine gene expression patterns in PBMC of  HIV/HCV co-infected patients to identify biological processes that distinguish responders from non-responders following 48 weeks of peg-interferon-α-2b and ribavirin therapy.

Methods:  PBMC gene expression profiles from 15 patients pre- and post-anti-HCV therapy were determined using the Affymetrix U133A GeneChip (~22,000 genes). Patients were grouped as either non-responders (n = 5), relapsers (n = 7), or responders (n = 3) based on HCV viral load following therapy. Gene expression values were determined using MAS5 and significant differences in gene expression determined by ANOVA. Differentially expressed genes were grouped using K-means clustering and functional category enrichment was performed using EASE analysis.

Results:  By treatment in all patient groups, 75 genes were induced and were significantly associated (p <0.0001) with interferon induction, immune response, and anti-viral response gene classification terms. Pre-therapy levels of these genes were highest in non-responders suggesting an elevated state of immune activation in these patients. A cluster of 278 genes exclusively up-regulated in non-responders prior to therapy also contained genes associated with immune activation. Elevated immune activation in non-responders prior to therapy was confirmed by flow cytometric analysis and clinical monitor assays which showed elevated levels %CD4⁺CD25⁺ cells, %CD4⁺CD45RO⁺ cells, B cell numbers, serum ALT, and serum AST. No relationship to HCV genotype was found among the patient groups.

Conclusions:  Increased levels of immune activation in HIV-infected patients have been associated with poor prognosis and resistance to HAART and IL-2 therapy. Gene expression and clinical monitoring profiling of samples from HIV/HCV-co-infected patients also suggests a link between elevated immune activation and resistance to anti-HCV therapy and may provide a means to predict, in advance of treatment, which patients will fail anti-HCV therapy. The increase immune activation state induced by HIV-1 infection may explain the lower response rate to HCV therapy in HIV-infected patients.

Keywords: microarray; immune activation; HCV therapy