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Recently, Baggio-Zappia et al. (2011) reported the ef -fects of GB virus C (GBV-C) on interleukin (IL)-2 and interferon (IFN)-γ in CD4 and CD8 T cells. GBV-C coin -fection was not associated with lower immune activation in human immunodeficiency virus (HIV)-positive indi -viduals as measured by CD38 expression per cell and IL-2 and IFN-γ expressing cells in their study. We agree with Baggio-Zappia et al. (2011) that “several factors, such as differences in the study populations, the stage of HIV in -fection and the time of GBV-C acquisition, may account for the discrepant results reported by different research groups”. However, two major factors may confound inter -pretation of the results reported by Baggio-Zappia et al. and provide the most likely explanation for the discrepant results observed between this study and previous reports (Maidana-Giret et al. 2009, Baggio-Zappia et al. 2011).First, approximately 85% of the subjects studied were on potent combination antiretroviral therapy (cART) and had nondetectable HIV RNA levels in their plasma. cART lowers T cell activation, raises CD4 counts, decreases HIV VL and thus interferes significantly with other fac -tors associated with HIV disease progression (Autran et al. 1997, Carcelain et al. 2001, Lederman 2001). Since the vast majority of subjects in the study of Baggio-Zappia et al. (2011) were effectively treated by cART, it is not surprising that GBV-C did not have an observed effect on the clinical variables studied (CD4, HIV VL etc.).Secondly, Baggio-Zappia et al. (2011) froze the periph -eral blood mononuclear cells (PBMCs) prior to conduct -ing in vitro studies of activation, IL-2 and IFN-γ cytokine production. Freeze-thawing PBMCs can alter detection of both surface marker expression and T cell function (Kvarn -strom et al. 2004, Mallone et al. 2011). By comparison, several groups found a reduction in CD38 on CD4 and/or CD8 T cells in HIV-infected subjects using fresh PBMCs (Bhattarai et al. 2011, Maidana-Giret et al. 2009). In addi -tion, HIV entry (chemokine) receptors CCR5 and CXCR4 are upregulated on CD4 and CD8 T cells following T cell activation (Smith et al. 2002). Three independent groups found reduced levels of CCR5 on CD4 cells using fresh, non-frozen PBMCs and one of these studies also found reduced levels of CXCR4 on CD4 cells (Nattermann et al. 2003, Maidana-Giret et al. 2009, Schwarze-Zander et al. 2010). Finally, IL-2 interactions with GBV-C have been demonstrated in vitro (George et al. 2003, Bhattarai 2011) and in vivo (Stapleton et al. 2009) using fresh, non-frozen cells for flow cytometry studies.Since cART will lower detection of cell surface mark-ers of T cell activation, making detection of a diminu-tion by GBV-C more difficult to detect, and since frozen PBMCs can alter levels of T cell activation markers, we believe that the study of Baggio-Zappia et al. (2011) does not negate the prior studies that used fresh PBMCs to evaluate T cell activation. However, the results illustrate the need for more direct and thorough studies of GBV-C on T cell function in individuals with HIV-infection.

Study design may explain discrepancies in GB virus C effects on interferon-γ and interleukin-2 production and CD38 expression in T lymphocytes