GB Virus C Infection Is Associated with Altered Lymphocyte Subset Distribution and Reduced T Cell Activation and Proliferation in HIV-Infected Individuals

Abstract

GBV-C infection is associated with prolonged survival and with reduced T cell activation in HIV-infected subjects not receiving combination antiretroviral therapy (cART). The relationship between GBV-C and T cell activation in HIV-infected subjects was examined. HIV-infected subjects on cART with non-detectable HIV viral load (VL) or cART naïve subjects were studied. GBV-C VL and HIV VL were determined. Cell surface markers of activation (CD38+/HLA-DR+), proliferation (Ki-67+), and HIV entry co-receptor expression (CCR5+ and CXCR4+) on total CD4+ and CD8+ T cells, and on naïve, central memory (CM), effector memory (EM), and effector CD4+ and CD8+ subpopulations were measured by flow cytometry. In subjects with suppressed HIV VL, GBV-C was consistently associated with reduced activation in naïve, CM, EM, and effector CD4+ cells. GBV-C was associated with reduced CD4+ and CD8+ T cell surface expression of activation and proliferation markers, independent of HIV VL classification. GBV-C was also associated with higher proportions of naïve CD4+ and CD8+ T cells, and with lower proportions of EM CD4+ and CD8+ T cells. In conclusion, GBV-C infection was associated with reduced activation of CD4+ and CD8+ T cells in both HIV viremic and HIV RNA suppressed patients. Those with GBV-C infection demonstrated an increased proportion of naive T cells and a reduction in T cell activation and proliferation independent of HIV VL classification, including those with suppressed HIV VL on cART. Since HIV pathogenesis is thought to be accelerated by T cell activation, these results may contribute to prolonged survival among HIV infected individuals co-infected with GBV-C. Furthermore, since cART therapy does not reduce T cell activation to levels seen in HIV-uninfected people, GBV-C infection may be beneficial for HIV-related diseases in those effectively treated with anti-HIV therapy.

Tropism of human pegivirus (formerly known as GB virus C/hepatitis G virus) and host immunomodulation: insights into a highly successful viral infection

“…The CD4 + T-cell count did not increase significantly in subjects with HPgV infection, whilst it increased by .1000 cells mm 23 in those without HPgV. In addition, the proportion of naive CD8 + and CD4 + T-cells is increased relative to memory and effector cells in individuals with persistent HPgV infection compared with HPgVnegative controls (Stapleton et al, 2012b). As IL-2 is required for proliferation and differentiation of T-cells, and HPgV inhibits T-cell activation and IL-2 production, we hypothesize that the CD8 + T-cell cytotoxic functions that control viral infections are reduced in those with HPgV infection, contributing to HPgV persistence and high serum viral loads (typically .10 7 copies ml 21 ) (Tillmann et al, 2001).…”

“…In contrast, HPgV envelope proteins do not have any hypervariable regions; the virus displays limited sequence variability within persistently infected hosts in protein regions predicted to be T-cell epitopes, and is associated with reduced T-cell activation and exhaustion (Mohr & Stapleton, 2009;Stapleton et al, 2012b …”

“…HPgV RNA was present in all 14 study subjects' PBMCs, and in highly purified populations of T-and Blymphocytes (.98 % purity), consistent with previous studies (George et al, 2006;Ruiz et al, 2010 Although HPgV replicates efficiently in humans, with mean serum viral loads typically .1610 7 genome equivalents ml 21 , replication is inefficient in vitro and the production of virus by lymphocytes maintained in culture ex vivo is reduced following T-cell activation (George et al, 2003;Rydze et al, 2012). Consistent with an interaction between HPgV and cell activation, several clinical studies observed a reduction in T-cell activation and proliferation markers in HIV-infected subjects with HPgV co-infection compared with HIV-mono-infected subjects (Bhattarai et al, 2012a;Maidana-Giret et al, 2009;Rydze et al, 2012;Stapleton et al, 2012b). Further evidence consistent with HPgV reducing inflammation comes from a recent report which found that HPgV infection was associated with reduced mortality in individuals infected with ebolavirus (Lauck et al, 2015).…”

GBV-C Infection and Risk of NHL among U.S. Adults

“…Furthermore, GBV-C infection has been associated with decreased apoptosis of T cells which may contribute to the prolonged survival of HIV-infected patients coinfected with GBV-C (14). Recent data showing that GBV-C infection reduces T cell activation and proliferation in HIV-infected individuals suggests that GBV-C infection may impair immune surveillance and immune responsiveness, which may lead to lymphomagenesis (15, 45, 46). …”

GB Virus C Coinfections in West African Ebola Patients

“…If GBV-C infection attenuates EBOV pathogenesis, it is possible that this occurs through modulation of the host immune response. In the context of HIV infection, GBV-C has been associated with a reduced production of proinflammatory cytokines and a reduction in T-cell activation in vivo and in vitro (34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44). Conversely, robust production of proinflammatory cytokines and lymphocyte activation followed by massive T-cell death are thought to play a major role in EBOV pathogenesis and have been associated with poor clinical outcome in retrospective studies (21)(22)(23)(24)(25)(26)(27).…”