GBV-C viremia is associated with reduced CD4 expansion in HIV-infected people receiving HAART and interleukin-2 therapy

Abstract

Objective Interleukin-2 (IL-2) is a cytokine with multiple effects on lymphocytes including induction of CD4+ T cell proliferation. IL-2 administration has been shown to increase CD4 counts in HIV-infected people receiving antiretroviral therapy. GB virus C (GBV-C) is an apparently non-pathogenic flavivirus that replicates in CD4+ T cells and inhibits HIV replication in vitro by mechanisms including downregulation of HIV entry coreceptors (CCR5 and CXCR4) and induction of chemokines (RANTES, MIP-1α, MIP-1β, and SDF-1). GBV-C replication is significantly inhibited in vitro by activation of primary CD4+ cell cultures with IL-2 and phytohemagglutinin. We sought to determine if there is an interaction between GBV-C and IL-2 in vivo. Methods GBV-C viremia status was characterized in 92 HIV-infected subjects participating in a randomized trial of IL-2 and antiretroviral therapy (AIDS Clinical Trials Group Study [ACTG] 328). Changes in CD4 cell counts and HIV RNA levels in subjects assigned IL-2 were compared with those in subjects assigned antiretroviral therapy alone. Results Subjects lacking GBV-C viremia had a significantly greater rise in CD4 count with IL-2, compared to GBV-C viremic subjects (by 511 cells/mm3 at week 84; interaction p=0.02): GBV-C viremic subjects assigned IL-2 did not demonstrate a significant increase in CD4 count compared to subjects not assigned to receive IL-2 (95% CI for difference -255 to 397 cells/mm3). Conclusions GBV-C viremia was associated with a block in CD4 cell expansion following IL-2 therapy in the ACTG 328 study, and GBV-C status may be an important factor in IL-2 treatment response.

GB virus C: the good boy virus?

“…IL-2 is a key cytokine that promotes T cell activation, proliferation and supports HIV replication (reviewed in [69]). GBV-C viremic subjects had significantly reduced response to IL-2 therapy compared to GBV-C non-viremic subjects [70] suggesting GBV-C infection may alter IL-2 signaling pathways and affect T cell activation. Consistent with this, Berzsenyi et al found that intra-hepatic T cell signaling is impaired in GBV-C coinfected (HCV− and HIV−) positive individuals [71].…”

“…In one study, GBV-C replication was diminished when PBMCs were cultured in IL-2 and PHA [7]. To examine the potential interaction between GBV-C and IL-2, study subjects participating in a prospective randomized trial of IL-2 were evaluated for GBV-C [70]. As in other studies, subjects randomized to receive intravenous (IV) IL-2 had significantly increased CD4 + T cell counts compared to those who received either subcutaneous IL-2 or no IL-2 [70].…”

“…To examine the potential interaction between GBV-C and IL-2, study subjects participating in a prospective randomized trial of IL-2 were evaluated for GBV-C [70]. As in other studies, subjects randomized to receive intravenous (IV) IL-2 had significantly increased CD4 + T cell counts compared to those who received either subcutaneous IL-2 or no IL-2 [70]. However, when stratified by GBV-C viremia status, subjects without GBV-C who received IV IL-2 had a significantly greater increase in CD4 counts compared to GBV-C viremic subjects (859 vs. 180 cell increase at week 60).…”

Human Pegivirus (HPgV; formerly known as GBV-C) inhibits IL-12 dependent natural killer cell function

“…Both HPgV and the phylogenetically related hepatitis C virus (HCV) can establish persistent human infection through complex mechanisms that are not completely characterized (Gutierrez et al, 1997;Tanaka et al, 1998;Williams et al, 2004;Burke and Cox, 2010;Lemon, 2010). In HIV-infected humans, persistent HPgV coinfection is associated with reduced T cell activation, proliferation and function (Maidana-Giret et al, 2009;Schwarze-Zander et al, 2010;Stapleton et al, , 2009 suggesting that HPgV-mediated immune modulation may contribute to viral persistence. In vitro, HPgV envelope glycoprotein (E2) inhibits T cell activation by reducing signaling through the IL-2 receptor and the T cell receptor (TCR), with resultant reduction in activation of the lymphocyte specific tyrosine kinase (Lck) (Bhattarai et al, 2013).…”

Current Views on the Pathophysiology of GB Virus C Coinfection with HIV-1 Infection

“…Notably, GBV-C and HIV coinfection of lymphocytes also appears to inhibit the replication of R5-and X4-tropic HIV [11,36,37]. However, the exogenous addition of IL-2 and PHA to GBV-C-infected lymphocyte cultures resulted in decreased GBV-C replication [38]. Although at present it is understood that spleen and bone marrow are the primary sites of replication [39], investigations are underway to completely exclude the role of other sites and cells, especially liver cells, as possible sites of replication.…”