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. Author manuscript; available in PMC: 2013 Jul 10.
Published in final edited form as: Mem Inst Oswaldo Cruz. 2012 Jun;107(4):568–569. doi: 10.1590/s0074-02762012000400023

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

Nirjal Bhattarai 1,2, Jack T Stapleton 1,2,+
PMCID: PMC3707606  NIHMSID: NIHMS481844  PMID: 22666874

Recently, Baggio-Zappia et al. (2011) reported the effects of GB virus C (GBV-C) on interleukin (IL)-2 and interferon (IFN)-γ in CD4 and CD8 T cells. GBV-C coinfection was not associated with lower immune activation in human immunodeficiency virus (HIV)-positive individuals 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 infection and the time of GBV-C acquisition, may account for the discrepant results reported by different research groups”. However, two major factors may confound interpretation 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 factors 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 peripheral blood mononuclear cells (PBMCs) prior to conducting 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 (Kvarnstrom 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 addition, 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 markers of T cell activation, making detection of a diminution 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.

This is a commentary on article Baggio-Zappia GL, Barbosa Ade J, Brunialti MK, Salomão R, Granato CF. Influence of GB virus C on IFN-γ and IL-2 production and CD38 expression in T lymphocytes from chronically HIV-infected and HIV-HCV-co-infected patients. Mem Inst Oswaldo Cruz. . 2011;106(6):662-9.

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