GB Virus C E2 Inhibits PD-1-Mediated T Cell Signaling Dysfunction during Chronic Viral Infection

Background: Program death receptor 1 (PD-1) is a co-inhibitory receptor that is upregulated and contributes to T cell dysfunction (exhaustion) during chronic viral infections, including HIV and HCV. GB virus C (GBV-C) is a persistent human virus, and co-infection is associated with reduced immune activation and improved clinical outcomes in HIV- and Ebola-infected individuals. Methods: PD-1 levels were measured by flow cytometry on CD38+ T cells from 45 HIV-infected individuals, 20 of whom were co-infected with GBV-C. Jurkat cell lines that stably express GBV-C E2 protein and vector control were used to purify total cellular RNA before, and 24 h following, activation using anti-CD3/CD28 treatment. Gene expression was analyzed by RNA-seq and qRT-PCR. Results: HIV-infected individuals with GBV-C viremia had reduced PD-1 expression on activated CD4+ and CD8+ T cells compared to HIV-infected GBV-C negative individuals. GBV-C particles and GBV-C E2 protein each inhibited PD-1 expression on T cells in vitro. Consistent with this, GBV-C E2 reduced gene expression of PD-1, and its ligand PD-L1, in both resting and activated T cells. GBV-C E2 regulated transcription of the PD-1 signaling pathway and T cell activation associated genes, without downregulation of the interferon-stimulated and innate immunity-related genes needed to resolve viral infections. Conclusions: Our current understanding of chronic RNA virus infections is that upregulation of PD-1 with T cell exhaustion is critical for viral persistence. However, these data demonstrate that GBV-C infection reduced PD-1 expression on activated T cells during HIV infection, and that the GBV-C E2 protein inhibits PD-1 signaling in T cells. This may preserve T cell function and contribute to the lack of immune deficiency in people with chronic GBV-C infection. Understanding the mechanisms by which GBV-C E2 alters PD-1 signaling may aid in the development of novel immunomodulatory therapeutics to prevent T cell dysfunction (exhaustion) during chronic viral infections.

Hepatitis viruses (excluding hepatitis C virus)

Viral hepatitis is an ancient disease which remains a major health problem worldwide. The group of hepatitis viruses includes five unrelated human viruses (A to E), which differ in their genome organization, biology, and epidemiology, while being united by their hepatotropism. About 10–15% of cases of viral hepatitis are considered as non-A to E hepatitis, whose aetiology is still unknown, but the search for which has led to the identification of several new viruses (e.g. hepatitis G virus or GB virus-C, TT, and SEN viruses) of uncertain pathogenic significance. Thus, the search for new hepatitis agents responsible for the small proportion of cases with cryptogenic hepatitis continues.

Inhibición de VIH-1 por GB Virus C

Inhibición de VIH-1 por GB Virus C Inhibition of VIH-1 by GBVC Gibran Horemheb-Rubio, Cruz Vargas-De-León, Guillermo Gómez-Alcaraz, Ernesto J Ramirez Lizardo, David Kershenobich Stalnikowitz Unidad de Medicina Experimental, UNAM, Hospital General de México, Secretaría de Salud. Unidad Académica de Matemáticas, UAGro, Guerrero, México, Facultad de Estudios Superiores Zaragoza, UNAM, México. Facultad de Ciencias, UNAM, México. Departamento de Fisiología CUCS U de G. DOI: https://doi.org/10.33017/RevECIPeru2011.0006/ RESUMEN El GB virus C (GBVC) es un virus linfotrófico de ARN positivo, al cual hasta el momento no se le ha asociado patología alguna. El GBV-C se ha encontrado en porcentajes importantes en donadores de sangre sanos, y en promedio se encuentra en el 1.7% de la población. La forma en que este virus se transmite, es muy similar a las vías de transmisión de VIH y HCV, es decir, por vía parenteral, transmisión sexual, incluso se ha estudiado la vía vertical de transmisión y de lactancia materna. Se replica en células sanguíneas, predominantemente en células mononucleares de sangre periférica, en su mayoría en células T (CD4+ y CD8+) y B. El VIH, es el virus que provoca el SIDA, para el cual hasta el momento no tenemos una cura o vacuna, sin embargo, las interacciones entre GBV-C y VIH, han demostrado en los estudios clínicos realizados hasta el día de hoy una progresión más lenta hacia SIDA y por lo tanto una mayor sobrevida y en estudios in vitro, GBV-C es capaz de inhibir in vitro a VIH en un rango del 78% al 98%; sin que hasta el momento se hayan descrito en detalle los mecanismos de esta interacción. En este trabajo construimos un modelo matemático que describe la dinámica de inhibición del VIH por el virus GBV-C. Se desarrolla un sistema de seis ecuaciones diferenciales no lineales que incluye la población de células susceptibles (sanas), células únicamente infectadas (por GBV-C y VIH, respectivamente), partículas virales libres (GBV-C y VIH) y células doblemente infectadas por GBV-C y VIH. El análisis del modelo revela la existencia de cuatro puntos de equilibrio: el punto de equilibrio libre de la infección en el que no hay virus; el punto de equilibrio infectado por el virus GBV-C; el punto de equilibrio infectado por el virus VIH; y otro punto de equilibrio de células infectadas donde coexisten las dos poblaciones virales. Se establece la estabilidad local de los puntos de equilibrios. Se realizan simulaciones numéricas con parámetros obtenidos de la literatura algunos sugeridos por los autores y que complementan los resultados teóricos. Descriptores: VIH, GB Virus C, Inhibición, modelo matemático, estabilidad. ABSTRACT GB virus C (GBV-C) is a lymphotropic, positive-RNA virus. GBV-C has been found in considerable amounts in healthy blood donors and, in average, it is found in 1.7% of the population. Its transmission is very similar to HIV and HCV i.e. by parental and sexual transmission. The possibility of transmission via breastfeeding has been suggested. GBV-C replicates in mononuclear blood cells, mainly in T (CD4+ and CD8+) and B cells. HIV is a world health problem that until today we don’t have a cure or vaccine. GBV-C and HIV interactions have prove that coinfected patients have slower progression to AIDS and longer survival, in vitro coinfection experiments GBV-C makes a inhibition of HIV replication in the range of 78% – 98%, but there is no description of the specific mechanism of this interaction. In this paper, we propose a mathematical model describing the inhibition of HIV by GBV-C. This model consists of six non-linear differential equations system taking into account healthy cells, cells infected exclusively by HIV or GBV-C, free GBV-C and HIV viral particles and by cells coinfected by GBV-C and HIV. The analysis reveals the existence of four equilibria: one equilibrium free of any infection, another one infected by GBV-C, one HIV infected equilibrium and an equilibrium of coinfected cells. A local stability analysis was carried out as well as numerical simulations with parameter values taken from the literature. Keywords: VIH, GB Virus C, Inhibition, mathematical model, stability.

Divergent Pro-Inflammatory Cytokine Response Induced by GB Virus C/ Hepatitis G virus (GBV-C/HGV) and Torque Teno Virus (TTV) Co-Infections in Hepatitis C Virus (HCV) Infected Thalassemia Patients

Despite common incidence of GB virus C/Hepatitis G virus (GBV-C/HGV) and Torque Teno Virus (TTV) co-infections in subjects with Hepatitis C virus (HCV) infection, pathogenic role of these co-infections in HCV infected subjects has not been clear since studies have mostly been based on liver enzyme profile yielding variable results. Pro-inflammatory cytokines that participate in host immune response against viruses are generated as a consequence of triggering of related genes by Nuclear Factor Kappa B (NF-kB) that is a member of transcription family. Study of three pro-inflammatory cytokines e.g. interleukin 1 beta (IL-1β), Interleukin-6 (IL-6), interleukin-8 (IL-8) in a group of multi-transfused thalassemic subjects in relation to positivity for HCV, HGV and TTV infections showed elevated levels of these cytokines in serum as well as in supernatant of peripheral blood mononuclear cell (PBMCs) cultures in HCV-GBV-C/HGV co-infected subgroup compared to HCV mono-infected subgroup (p <0.05 for comparison of all three cytokines) while HCV-TTV co-infected subgroup showed lowering of these levels compared to HCV mono-infected subgroup (p <0.05 for comparison of all three cytokines). Levels of p65 component of NF-kB i.e.NF-kB p65 in nuclear extracts of lipopolysaccharide stimulated PBMCs correlated positively with the levels of pro-inflammatory cytokines in serum as well as that in supernatants of PBMC cultures in both HCV- GBV-C/HGV co-infected and HCV-TTV co-infected subgroups (p values ranging from <0.001 to 0.004). Levels of NF-kB p65 in nuclear extracts and levels of pro-inflammatory cytokines in serum as well as in supernatants of PBMC culture did not show any alteration compared to thalassemic subjects with HGV or TTV infections alone and healthy non-transfused subjects. Based on the inhibitory role of TTV on activation of NF-kB in TTV-HCV co-infected cases observed in the present study and the reported contribution of NF-kB towards development of hepatocellular carcinoma (HCC) due to establishment of chronicity, it may be worth evaluating if TTV or any component of TTV can be utilized as therapeutic vaccine against development of HCC in HCV infected subjects.