GB virus C: the good boy virus?

Human pegivirus (HPgV; previously called GB virus C/hepatitis G virus) has limited pathogenicity, despite causing persistent infection, and is associated with prolonged survival in human immunodeficiency virus-infected individuals. Although HPgV RNA is found in and produced by T- and B-lymphocytes, the primary permissive cell type(s) are unknown. We quantified HPgV RNA in highly purified CD4+ and CD8+ T-cells, including naive, central memory and effector memory populations, and in B-cells (CD19+), NK cells (CD56+) and monocytes (CD14+) using real-time reverse transcription-PCR. Single-genome sequencing was performed on viruses within individual cell types to estimate genetic diversity among cell populations. HPgV RNA was present in CD4+ and CD8+ T-lymphocytes (nine of nine subjects), B-lymphocytes (seven of ten subjects), NK cells and monocytes (both four of five). HPgV RNA levels were higher in naive (CD45RA+) CD4+ cells than in central memory and effector memory cells (P<0.01). HPgV sequences were highly conserved among subjects (0.117±0.02 substitutions per site; range 0.58–0.14) and within subjects (0.006±0.003 substitutions per site; range 0.006–0.010). The non-synonymous/synonymous substitution ratio was 0.07, suggesting a low selective pressure. Carboxyfluorescein succinimidyl ester (CFSE)-labelled HPgV RNA-containing particles precipitated by a commercial exosome isolation reagent delivered CSFE to uninfected monocytes, NK cells and T- and B-lymphocytes, and HPgV RNA was transferred to PBMCs with evidence of subsequent virus replication. Thus, HPgV RNA-containing serum particles including microvesicles may contribute to delivery of HPgV to PBMCs in vivo, explaining the apparent broad tropism of this persistent human RNA virus.

Human pegivirus RNA is found in multiple blood mononuclear cells in vivo and serum-derived viral RNA-containing particles are infectious in vitro

GB virus C (GBV-C) is prevalent globally and particularly among individuals at risk of parental exposures. Based on genetic diversity, this virus is now classified into six genotypes and many subtypes with distinct geographical distribution. In this study, 120 Injecting Drug Users (IDUs) were recruited from Yunnan province, China. Among them, 43 (35.8%) were positive for GBV-C RNA, 70 (58.3%) and 103 (85.8%) sero-positive for HIV-1 and HCV respectively. This revealed 18.3% of IDUs having GBV-C/HIV/HCV triple infection, which is significantly higher than 7.5% of GBV-C/HIV-1 and 10% of GBV-C/HCV dual infection rates (P<0.05). Based on 5′UTR sequences, the identified 43 viral isolates can be classified into three phylogenetic groups: one (2.3%) and two (4.7%) belonged to genotype 3 and 4, respectively, and the remaining 40 (93%) formed a new group with 97% of bootstrap support. This new GBV-C group was further confirmed by characterizing the E2 region and full-length genome sequences. Analysis of 187 nt 5′UTR sequence showed three previous reported isolates from Southeast Asia were re-classified into this new group. It implies they have the same origin with strains from Yunnan. Although we provisionally assigned this new group as GBV-C genotype 7, a simpler five groups of GBV-C nomenclature is recommended. Genotype 4, 6 and the newly designated genotype 7 could be reclassified as one group, which may represent a single GBV-C genotype. The classification of the other four groups was corresponding to that of previous reported genotype 1, 2, 3 and 5. Furthermore, the diversity of amino acid sequence in the E2 region was analyzed. The inhibitory effect of GBV-C genotype 7 on HIV-1 cell entry could be deduced. Since GBV-C may have a beneficial effect on AIDS disease progression and interact with HCV during co-infection, this finding may raise interests in future studies on this virus that was previously thought to be a “non-pathogenic virus”.

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A novel genotype of GB virus C: its identification and predominance among injecting drug users in Yunnan, China.

Eight virus families whose members infect vertebrates are currently known to possess single-stranded, positive-sense RNA genomes: the families Picornaviridae, Caliciviridae and Hepeviridae have non-enveloped capsids, whereas the families Flaviviridae, Togaviridae, Arteriviridae and Coronaviridae are characterized by enveloped capsids. They all have in common the property of using their own genome as messenger RNA (mRNA), from which they synthesize one or several polyproteins that are subsequently cleaved into individual proteins by viral or cellular proteases. These viruses possess the genetic information for the synthesis of an RNA-dependent RNA polymerase. This enzyme transcribes the positive RNA strand as well as the complementary negative RNA strands, which arise as intermediate products of genome replication. In the course of this process, the new genomic RNA molecules are generated from the second transcription step. The classification into the different taxonomic families depends on the number, size, position and orientation of viral genes in the RNA molecule, the number of different polyproteins that are synthesized during viral infection and the existence of an envelope as a virion component.

Viruses with Single-Stranded, Positive-Sense RNA Genomes

Viral infections alter host cell homeostasis and this may lead to immune evasion and/or interfere with the replication of other microbes in coinfected hosts. Two flaviviruses are associated with a reduction in HIV replication or improved survival in HIV-infected people (dengue virus (DV) and GB virus type C (GBV-C)). GBV-C infection and expression of the GBV-C nonstructural protein 5A (NS5A) and the DV NS5 protein in CD4(+) T cells inhibit HIV replication in vitro. To determine whether the inhibitory effect on HIV replication is conserved among other flaviviruses and to characterize mechanism(s) of HIV inhibition, the NS5 proteins of GBV-C, DV, hepatitis C virus, West Nile virus, and yellow fever virus (YFV; vaccine strain 17D) were expressed in CD4(+) T cells. All NS5 proteins inhibited HIV replication. This correlated with decreased steady-state CD4 mRNA levels and reduced cell surface CD4 protein expression. Infection of CD4(+) T cells and macrophages with YFV (17D vaccine strain) also inhibited HIV replication and decreased CD4 gene expression. In contrast, mumps virus was not inhibited by the expression of flavivirus NS5 protein or by YFV infection, and mumps infection did not alter CD4 mRNA or protein levels. In summary, CD4 gene expression is decreased by all human flavivirus NS5 proteins studied. CD4 regulation by flaviviruses may interfere with innate and adaptive immunity and contribute to in vitro HIV replication inhibition. Characterization of the mechanisms by which flaviviruses regulate CD4 expression may lead to novel therapeutic strategies for HIV and immunological diseases.

/pdf/viruses-within-the-flaviviridae-decrease-cd4-expression-and-2oyayh385v.pdf

Viruses within the Flaviviridae decrease CD4 expression and inhibit HIV replication in human CD4+ cells.

Objective: A number of studies concerning the pathogenesis of GB virus C (GBV-C) in HIV-infected people suggest a beneficial effect and improved survival for dually infected individuals. However there has remained controversy regarding the clinical relevance of these findings, as some studies have not confirmed these observations. To address the possibility of direct inhibitory mechanisms, we studied the impact of GBV-C on HIV-1 replication in vitro. Methods: Peripheral blood mononuclear cells (PBMC) were infected with sera from GBV-C positive individuals or transfected with GBV-C specific RNA and superinfected with HIV. Replication kinetics of HIV were studied by quantification of HIV-p24 release. Induction of soluble antiretroviral factors were monitored with an HIV infection assay and by quantification of chemokine secretion. Changes in chemokine receptor expression were analysed by flow cytometry. Results: We demonstrate that GBV-C infection of PBMC leads to significant replication inhibition of R5- and X4-HIV isolates representing eight HIV clades. The inhibitory effect is mediated by GBV-C infection and also by expression of GBV-C structural glycoproteins and/or of non-structural proteins NS2/NS3. Upon GBV-C infection CD4 and CD8 T lymphocytes produce soluble HIV-suppression factors. Induction of stromal cell-derived factor (SDF)-1 and subsequent internalization of CXCR4 was not observed. Conclusions: CD4 and CD8 T lymphocytes are stimulated by GBV-C to secrete antiretroviral factors, inhibiting R5- and X4-HIV strains. As no induction of SDF-1 and no down-regulation of the respective receptor CXCR4 could be observed, it is likely that additional unidentified factors causing inhibition of X4-HIV strains are induced by GBV-C.

Inhibition of HIV strains by GB virus C in cell culture can be mediated by CD4 and CD8 T-lymphocyte derived soluble factors.

Epidemiological studies have revealed an association between GB virus C (GBV-C) long-term viraemia and ameliorated HIV disease progression. We have provided evidence that a single protein of GBV-C, the glycoprotein E2, interferes with early HIV replication steps of both X4- and R5-tropic HIV strains. Preincubation with anti-E2 antibody specifically abrogates the inhibitory effect. Results were confirmed by the in-vitro expression of GBV-C E1/E2 encoding RNA.

HIV entry inhibition by the envelope 2 glycoprotein of GB virus C.

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Inhibition of HIV strains by GB virus C in cell culture can be mediated by CD4 and CD8 T-lymphocyte derived soluble factors.

HIV entry inhibition by the envelope 2 glycoprotein of GB virus C.