Activation of Interferon Response Genes and of Plasmacytoid Dendritic Cells in HIV-1 Positive Subjects with GB Virus C Co-Infection

Abstract

GB virus C (GBV-C) coinfection has a protective role in Human Immunodeficiency Virus (HIV) infection, and increases the duration of suppression of HIV-1 viremia in patients under Highly Active Anti-Retroviral Therapy (HAART). Since innate antiviral response may be involved in the protection, we analyzed the possible role of GBV-C as activator of innate immunity. To this aim, we measured the extent of activation of the interferon (IFN) system and of circulating Dendritic Cells (DC) in vivo, and the ability of GBV-C to activate these functions in vitro. Activation of IFN system and of circulating DC was compared in GBV-positive and -negative HIV-1 co-infected patients with HAART-driven suppression of HIV-1 viremia. Endogenous levels of IFN-γ and RNA-dependent protein kinase (PKR) mRNA were significantly higher in peripheral blood mononuclear cells (PBMC) from GBV-C-positive when compared to GBV-C-negative patients. IFN-γ expression was correlated with all the Interferon response genes (IRGs) and with GBV-C viremia. The frequency of circulating plasmacytoid DC (pDC) expressing the CD80 activation marker was increased in GBV-C-positive patients, and was correlated with GBV-C viral load. In vitro experiments indicated that GBV-C is able to induce IFN-γ expression in PBMC. In addition, in PBMC cultures GBV-C induced an increase of CD80 expression by pDC, that was reduced by antibody to IFN-γ. Our data indicate that in HIV-positive patients GBV-C coinfection promotes the activation of IFN-γ and downstream IRG expression, as well as with the activation/maturation of circulating pDC. GBV-C-driven IFN-γ activation is, at least in part, responsible for the increased maturation of pDC. This crosstalk may suggest a role for GBV-C coinfection in boosting the innate antiviral response to HIV infection.

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

“…In that study, researchers also found an intermediate protective role for antibodies specific for the E2 protein of GBV-C. Studies conducted in the highly active antiretroviral therapy (HAART) era have demonstrated that GBV-C is associated with lower rates of HIV rebound after HAART-driven virological success (Antonucci et al 2005, Souza et al 2006. Several mechanisms have been proposed to explain the putative effect of GBV-C on the course of HIV disease, such as increased secretion of the chemokines regulated on activation, normal T cell expressed and secreted (Nattermann et al 2003), macrophage inflammatory protein (MIP)-1α, MIP-1β and stromal cell-derived factor-1, reduced expression of the chemokine receptors CCR5 and CXCR4 (Xiang et al 2004), preservation of the Th1 cytokine profile (Sathar et al 2004), activation of the interferon (IFN) gene system (Capobianchi et al 2006), increased frequency of plasmacytoid dendritic cells expressing CD80 (Lalle et al 2008) and decreased T cell activation (Maidana-Giret et al 2009). In contrast, other studies have failed to demonstrate an influence of GBV-C on the course of HIV infection (Quiros-Roldan et al 2002, Jung et al 2005, Van der Bij et al 2005, Haji Molla Hoseini et al 2007), while at least one report concluded that GBV-C viremia tended to worsen rather than improve mortality among the co-infected patients (Brust et al 2002).…”

Molecular Evolution of Hepatitis Viruses

“…This effect may reduce a successful HIV-1 interaction with infected cell (Xiang, 2004). Several lines of evidence suggest a possible inhibition of HIV-1 by GBV-C through increase in soluble ligands for HIV-1 correceptor and activation of innate immunity (Lalle, 2008;Mohr & Stapleton, 2009). In addition, the beneficial effect of GBV-C on survival of HIV-1 infected patients might be genotype specific (Schwarze-Zander et al, 2006).…”

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

“…Recent studies showed that HIV-1 patients coinfected with GBV-C have a higher percentage of CD80 + mature pDCs, which might contribute to effective control of HIV-1 [50]. Evidence also exists that GBV-C infection in HIV-infected patients could lead to the activation of IFN genes [19]. Investigations of GBV-C-positive and GBV-C-negative HIV-infected patients showed that the expression of IFN genes 2-5-OAS, MxA, IFN AR-1, and PKR were relatively increased in HIV-GBV-C coinfected cases.…”

“…Recent reports are also suggestive of improved initial response to antiretroviral regimens [17] and sustained suppression of HIV viral loads for prolonged periods [18]. Studies also associate the role of GBV-C in increasing interferon-γ (IFN-γ) and plasmacytoid dendritic cell (pDC) maturation to mediate innate antiviral immune responses in the host [19,20]. The disease attributes underlying HIV-1/GBV-C coinfection need to be discussed in detail; therefore, we reviewed the published literature for recent research findings on the pathophysiology of GBV-C infection and its impact on HIV disease progression.…”