GBV-C co-infection in HIV patients downregulates CCR5 and CXCR4 surface expression on CD4 cells

Aims: The flavivirus GB virus-C (GBV-C), thus far not known to cause any disease, has been shown to be associated with delayed progression of HIV disease. Recently, in vitro studies demonstrated down-regulation of CCR5 as a potential mechanism of GBV-C to modulate HIV disease progression. We therefore studied surface expression of the two major HIV co-receptors, CCR5 and CXCR4, on CD4+ and CD8+ T-cells in 110 HIV patients stratified with respect to their GBV-C status and immune function. Methods: GBV-C infection was studied in 110 HIV patients by RT-PCR. CCR5Δ32 mutation was analyzed by real time PCR. FACS analysis was used to measure CCR5 and CXCR4 surface expression on CD4+ and CD8+ T-cells. Results: GBV-C RNA replication was detected in 31% (34/110) of patients. Fourteen patients were excluded from the analysis because of reduced CCR5 surface expression due to a heterozygous CCR5Δ32 mutation. In the remaining HIV/GBV-C co-infected patients with CD4 <350/μl CCR5 and CXCR4 expression on CD4+ T-cells was significantly reduced to 77% and 80%, respectively, of the levels measured in HIV mono-infected patients (p<0.05). In contrast, HIV-monoinfected and HIV/GBV-C co-infected patients did not differ with respect to CCR5 and CXCR4 expression on CD4+ T cells in the subgroup with preserved immune function (CD4>350/µl) and on CD8+T cells independent of immune function. Of note, we also found significant downregulation of CXCR4 (78%; p<0.05), but not CCR5 expression on CD4+ T-cells in HIV/GBV-C co-infected patients with detectable HIV replication compared to HIV mono-infected patients. Conclusions: GBV-C co-infection is common in HIV infected patients and is associated with reduced expression of both major HIV co-receptors on CD4+ T-cells in the subset of HIV patients with poorly controlled HIV replication and advanced immunodeficiency. Therefore, the molecular and cellular mechanisms underlying down-regulation of HIV co-receptors by GBV-C merit further investigation.

CCR5 - CXCR4 - GBV-C - HIV