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Matthias Stoll

Almost one century ago, in 1917, the Austrian neurologist Julius Wagner von Jauregg was able to obtain improvement in patients with late stage symptomatic neurosyphilis, by infecting them with the malaria parasite. This approach might appear strange to physicians in the contemporary era of antimicrobial treatment. However, at that time it was by far the most effective option and it earned its discoverer the Nobel Prize for Medicine in 1927. Thus, even an infection with obligatory pathogens may result in harm reduction under certain conditions.

GB virus C is a flavivirus that is closely related to hepatitis C virus. The name GB virus stems from early experiments on the transmission of acute hepatitis from humans to marmoset monkeys. One of the first source patients had the initials "G.B." and was a 34-year old colleague of the author of the experiment (Deinhardt 1967). Later on, two hepatotropic viruses, GB virus A (GBV-A) and GB virus B (GBV-B), were isolated from these monkeys. Two independent research groups simultaneously discovered the related GB virus C (GBV-C) in humans with hepatitis in the middle of the 1990s. Subsequently, the GB virus C has promoted the discussion as to whether the natural course of HIV infection might be modulated in a favorable way by this particular coinfection. In addition, because GBV-C was first found in humans with hepatitis, and due to its close relationship to the hepatitic GBV-A and GBV-B viruses, GBV-C was also called "hepatitis G virus (HGV)" by one research group. This name should no longer be used, because it has since been shown that GBV-C neither causes hepatitis nor worsens preexisting hepatitis (Berenguer 1996, Tillmann 1998, Rambusch 1998, Stark 1999). In fact, GBV-C is not a hepatotropic but a lymphotropic virus. Despite intensive research, GBV-C has not been shown to cause any other known disease.

The virus can be found in six different genotypes (Muerhoff 2006) and it is frequently and worldwide found in humans: approximately 10 to 40 % of blood donors have specific antibodies against GBV-C and up to 5 % of them show GBV-C virus replication. Assuming that the virus is apathogenic, affected individuals are not excluded from the donation of blood and consequently, serological diagnostics on GBV-C are not routinely performed. Two serological markers for GBV-C infection exist: GBV-C viremia is determined using a PCR method; and antibodies to the envelope region E2 (anti-E2) are detected by ELISA. As they are mutually exclusive, either GBV-C viremia or the presence of anti-E2 is detectable in GBV-C infected individuals. In most cases, GBV-C viremia is transient and ends with seroconversion to anti-E2, resulting in immunity to new infections. However, this does not seem to be a lifelong immunity (Table 1). Transmission of GBV-C occurs parenterally and mucosally, thus similar to HIV, HBV and HCV infections.

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GBV-C: Harmless or rather a friendly virus? The first report of decreased HIV disease progression and mortality in GBV-C coinfected patients was from a German monocentric study, published in 1998. Initially, these results did not draw much attention, although they were confirmed by other working groups (Toyoda 1998, Heringlake 1998). Later on, longer follow-ups revealed again a favorable prognosis for HIV-infected individuals with GBV-C viremia (Tillmann 2001, Xiang 2001). These results encountered considerable resonance in the international press - and articles in some newspapers reported in a vociferous manner a "miracle virus, which stops AIDS". As a consequence, some patients requested sources of supply for GB virus C from their physicians and wanted to infect themselves with it. In summary, the GBV-C story became involuntarily discredited by a couple of simplified and unscientific reports in the secondary literature. Concomitantly, a controversial discussion of the data started within the scientific community. In recent years, however, several studies have focused on the influence of GBV-C status on surrogate markers and clinical progression in HIV infection. Table 1: Serological markers and stages of GBV-C infection Marker: GBV-C-Viremia (RNA) Anti-E2-Antibodies Method: PCR / b-DNA ELISA GBV-C negative negative negative Replicative GBV-C Infection positive negative Past GBV-C Infection negative positive The heterogeneity of the HIV/GBV-C coinfected cohorts is a major methodical problem in an attempt to compare the results from the different studies published recently. Some studies did not follow up the status of the GBV-C viremia longitudinally. The serological status of GBV-C, however, can change over time, and the distinction between the three possible stages of GBV-C serostatus is crucial for the interpretation of the studies (see table 1). Overall, it is agreed that there is no difference between the clinical course of HIV-infected individuals without contact to the GB virus C (GBV-C negative) and those with cleared GBV-C infection (anti-E2-positive). But GBV-C viremia (GBV-C RNA positive) is prolonged in HIV infection. Persistence of GBV-C RNA in HIV-positive patients was associated with less rapid progression of clinical disease, lower death rates, smaller reduction in CD4 T cells, reduced increase in HIV plasma viremia, and improved quality of life - in comparison with HIV-infected individuals without GBV-C viremia in a meta-analysis (Zhang HIV Med 2006). These effects were more pronounced in studies with longer follow-up periods. Confirmatory results came up from additional data published later on (Handelsman 2006, Mosam 2007, Yirell 2007, Souza 2006, Li 2006) Prospective cohort studies are on the way, but still may need longer follow-up periods (Sheng 2007). However, some studies - partially with considerable follow-up time - could not confirm a beneficial effect of GBV-C viremia on HIV infection (Sabin 1998, Birk 2002, Bjorkman 2004, Kaye 2005, Williams 2005, van der Bij 2005, Ryt-Hansen 2006). These conflicting results might be explained by gender-specific effects, different GBV-C genotypes, overreporting of chronic GBV-C viremia due to missing follow-up of GBV-C viremia in the studies or by unknown reasons. Several studies have described more pronounced antiretroviral and immunological effects of antiretroviral therapy in HAART-treated GBV-C RNA positive patients (Bjorkman 2007). However, other studies did not find these differences (Tillmann 2005). But no study to date describes a negative influence of GBV-C viremia on the effect of HAART. Therefore, to summarize the various cohort studies it could be cautiously concluded that a favorable clinical long-term course of HIV infection in GBV-C RNA positive individuals may be restricted to patients with ongoing GBV-C replication. However, most studies were retrospective and performed in only a few centers. Therefore, at present, it cannot be completely excluded that the association between GBV-C viremia and ameliorated HIV infection is at least in part biased by other factors. The fundamental chicken-egg dilemma still remains unsolved: whether GBV-C viremia is an epiphenomenon or a cause for the different outcomes of HIV infection is not yet clear. But increasing evidence came up from various in vitro studies, that GBV-C interacts with HIV in a complex pattern. Proposed pathomechanisms: One question and multiple answers. A couple of immunomodulatory or antiviral mechanisms can be induced by GBV-C and may play an interacting role with HIV coinfection: in GBV-C-infected peripheral blood cells decreased expression of chemokine receptors (CCR5 and CXCR4) has been found on the surface of CD4+ and CD8+ T-cells. A potential pathomechanism for this down-regulation of chemokine receptors is the E2-protein-induced release of RANTES from T lymphocytes by its binding to the CD81 receptor (Tillmann 2002, Xiang 2004), independent to CD81-binding (Kaufmann 2007), or by other pathways (Jung 2007). Chemokine receptors are targets for HIV. Therefore, a result of decreased chemokine receptor expression is a decrease in HIV replication. Surprisingly, anti-E2 antibodies were also able to inhibit HIV replication in vitro (Xiang 2006b), which is in contrast to the observation that anti-E2 seroconversion accelerates the clinical HIV progression. Another study showed that a peptide consisting of a 85-amino acid subunit from NS5A (which is a viral protein from GBV-C) was able to induce RANTES in vitro and therefore down-regulates HIV replication (Xiang 2006a). Complex disturbances of the cytokine profile have been described in HIV-infected individuals in vivo, but are less prevalent in individuals with GBV-C/HIV coinfection (Nunnari 2003). Focusing on the innate immunity, normalized levels of CD69 (Fas-ligand) could be demonstrated on NK cells and were less pronounced on lymphocytes in GBV-C viremic HIV-infected individuals, resulting in down-regulation of apoptosis (Mönkemeyer 2006). Plasmacytoid dendritic cells, which play a major role in the T-cell mediated immune response against viral pathogens, have been found to be elevated in GBV-C+/HIV+ coinfected individuals (Bhatnagar 2007). In addition, further direct and indirect mechanisms of GBV-C or its components on HIV replication have been described. Contradictory extents of some effects of GBV-C on HIV in different cohorts could be due to different levels of lymphotropism of different GBV-C genotypes or to host-related factors (Jung 2007). How to deal with GBV-C-viremia in HIV-infection? The microbial zoo of pathogens of infectious diseases is crawling with lots of horrifying micro monsters, which can cause dreadful illnesses. In this frightening environment, the description of the little viral Tamagochi named GBV-C, which does not hurt its host and perhaps is able to protect him and to reduce harm caused by another infection, would be a nice fable. But beyond the tales of a potentially healthy infection at least three questions are still open: 1. GBV-C seems to play a complex causal role rather than its replication is only a secondary epiphenomenon, which is particularly frequent when HIV infection has a favorable clinical course for other reasons. But on which pathophysiological mechanisms is this based? 2. If we were able to define the pathways of GBV-C-associated modulation of HIV disease more in detail, how could we translate them into new therapeutic approaches? And last, but not least whilst this issue remains unsolved: 3. If persisting GBV-C viremia slows down the progression of an HIV coinfection, will it be of advantage to maintain a durable replication of GBV-C in these patients? Some authors favor the explanation that GBV-C viremia is an epiphenomenon of higher CD4+ T-cell counts. GBV-C replicates predominantly in CD4 T-lymphocytes and therefore it could be expected that the level of GBV-C viremia decreases if the helper T-cell counts drop (van der Bij 2005). This hypothesis, however, does not explain why HIV-infected patients should not be able to induce the CD4+ T-cell dependent specific humoral immune response against the E2 envelope protein of GBV-C with high CD4+ T-cell levels and how they are later able to do so with an impaired immunity. Initial evidence for a causal role of GBV-C came from in vitro experiments on GBV-C and HIV coinfected cell cultures (Xiang 2001). HIV replication in the cultured cells was decreased when the cells had been infected with GBV-C prior to HIV, but HIV replication remained on the same level when the cells were infected with GBV-C afterwards. Until now, little has been known about the factors relevant for maintenance or termination of GBV-C replication. The question had been risen, whether interferon treatment of hepatitis C - which is able to terminate GBV-C replication as well - could be harmful in GBV-C viremic HIV-/HCV-coinfected individuals. One study found no disadvantage in immunological and clinical surrogate-markers after interferon therapy but the results indicate differential effects of distinct GBV-C genotypes (Schwarze-Zander 2006). Two studies in HIV-2 infected individuals did not show an association between GBV-C viremia and disease progression, indicating as well a role of the genotype of HIV(Descamps 2006). GBV-C viremic HIV-positive individuals had a higher endogenous Interferon production, which might explain in part the beneficial effects on HIV progression (Capobianchi 2006). Further studies will be necessary to understand whether the clearance of GBV-C viremia induced by interferon therapy will have any impact on the course of HIV infection. Until then this issue is of potential impact for counseling in HIV, HCV, and GBV-C coinfection. But routine tests to determine the GBV-C status are still not available, and sensitivity and specifity of recent tests vary considerably (Souza 2006). Therefore, there is at least a need for screening for GBV-C serostatus, prospective follow-up, and individual counseling during interferon therapy and in controlled studies. The history of GBV-C, as well at that of HIV, is still young. Increasing insight into effects and mechanisms of HIV and GBV-C interaction and into the role of individual-specific host factors give the opportunity to elucidate clinically relevant regulation pathways of HIV. This could help us in the development of new therapeutic concepts prior to, or in addition to, HAART. Presumably, these concepts could be promising with respect to their clinical and therapeutic impact, because, in several studies, a benefit of GBV-C replication remained evident under HAART. References 1. Berenguer M, Terrault NA, Piatak M, et al. Hepatitis G virus infection in patients with hepatitis C virus infection undergoing liver transplantation. Gastroenterology 1996;111:1569-75. http://amedeo.com/lit.php?id=8942736 2. Birk M, Lindback S, Lidman C. No influence of GB virus C replication on the prognosis in a cohort of HIV-1-infected patients. AIDS 2002; 16: 2482-5. http://amedeo.com/lit.php?id=12461426 3. Bhatnagar N, Mönkemeyer M, Hong H, Schmidt RE, Heiken H. Plasmacytoid Dendritic Cells Expressing CD40 and CD83 Are Increased in HIV-1 Patients with GBV-C Co-infection. 14th CROI, San Francisco, 2007, Abstract 928 http://www.retroconference.org/2007/PDFs/928.pdf 4. Bjorkman P, Flamholc L, Naucler A, Molnegren V, Wallmark E, Widell A. GB virus C during the natural course of HIV-1 infection: viremia at diagnosis does not predict mortality. AIDS. 2004;18:877-86. http://amedeo.com/lit.php?id=15060435 5. Bjorkman P, Flamholc L, Molnegren V, Marshall A, Guner N, Widell A. Enhanced and resumed GB virus C replication in HIV-1-infected individuals receiving HAART. AIDS 2007;21:1641-1643. Abstract: http://amedeo.com/lit.php?id=17630561 6. Capobianchi MR, Lalle E, Martini F, et al. Influence of GBV-C infection on the endogenous activation of the IFN system in HIV-1 co-infected patients. Cell Mol Biol (Noisy-le-grand) 2006;52:3-8. Abstract: http://amedeo.com/lit.php?id=16914092 7. Deinhardt F, Holmes AW, Capps RB, Popper H. Studies on the transmission of human viral hepatitis to marmoset monkeys. I. Transmission of disease, serial passages, and description of liver lesions. J Exp Med 1967; 125: 673-88. http://amedeo.com/lit.php?id=4960092 8. Descamps D, Damond F, Benard A, et al. No association between GB virus C infection and disease progression in HIV-2-infected patients from the French ANRS HIV-2 cohort. AIDS 2006;20:1076-9. Abstract: http://amedeo.com/lit.php?id=16603866 9. Jung S, Eichenmüller M, Donhauser N, et al. HIV entry inhibition by the envelope 2 glycoprotein of GB virus C. AIDS 2007;21:645-7. Abstract: http://amedeo.com/lit.php?id=17314528 10. Handelsman E, Cheng I, Thompson B et al: The effect of maternal GBV-C infection on mother-to-child HIV transmission in the women and infant transmission study cohort. Abstract 718; 13th CROI 2006, Denver http://www.retroconference.org/2006/Abstracts/27753.htm 11. Heringlake S, Ockenga J, Tillmann HL, et al. GB virus C/hepatitis G virus infection: a favorable prognostic factor in human immunodeficiency virus-infected patients? J Infect Dis. 1998;177:1723-6. http://amedeo.com/lit.php?id=9607857 12. Kaufman TM, McLinden JH, Xiang J, Engel AM, Stapleton JT. The GBV-C envelope glycoprotein E2 does not interact specifically with CD81. AIDS 2007;21:1045-8. Abstract: http://amedeo.com/lit.php?id=17457101 13. Kaye S, Howard M, Alabi A, Hansmann A, Whittle H, van der Loeff HS. No observed effect of GB virus C coinfection in disease progression in a cohort of African woman infected with HIV-1 and HIV-2. Clin Infect Dis 2005;40:876-8. http://amedeo.com/lit.php?id=15736023 14. Lefrere JJ, Roudot-Thoraval F, Morand-Joubert L, et al. Carriage of GB virus C/hepatitis G virus RNA is associated with a slower immunologic, virologic, and clinical progression of HIV disease in coinfected persons. J Infect Dis 1999;179:783-9. http://amedeo.com/lit.php?id=10068572 15. Mosam A, Sathar MA, Dawood H, Cassol E, Esterhuizen TM, Coovadia HM. Effect of GB virus C co-infection on response to generic HAART in African patients with HIV-1 clade C infection. AIDS 2007;21:1377-9. Abstract: http://amedeo.com/lit.php?id=17545721 16. Mönkemeyer M, Heiken H, Schmidt R. Decreased fas expression on natural killer cells in GBV-C co-infected HIV-1 patients. Abstract 848, 13th CROI 2006, Denver. http://www.retroconference.org/2006/PDFs/848.pdf 17. Muerhoff AS, Dawson GJ, Desai SM. A previously unrecognized sixth genotype of GB virus C revealed by analysis of 5Ž-untranslated region sequences. J Med Virol 2006;78:105-11. Abstract: http://amedeo.com/lit.php?id=16299729 18. Nunnari G, Nigro L, Palermo F et al. Slower progression of HIV-1 infection in persons with GB virus C co-infection correlates with an intact T-helper 1 cytokine profile. Ann Intern Med 2003;139:26-30. http://amedeo.com/lit.php?id=12834315 19. Rambusch EG, Wedemeyer H, Tillmann HL, Heringlake S, Manns MP. Significance of coinfection with hepatitis G virus for chonic hepatitis C - a review of the literature. Z Gastroenterol 1998; 36: 41-53. http://amedeo.com/lit.php?id=9531689 20. Ryt-Hansen R, Katzenstein TL, Gerstoft J, Eugen-Olsen J. No influence of GB virus C on disease progression in a Danish cohort of HIV-infected men. AIDS Res Hum Retroviruses 2006;22:496-8. Abstract: http://amedeo.com/lit.php?id=16796523 21. Sabin CA, Devereux H, Kinson Z, et al. Effect of coinfection with hepatitis G virus on HIV disease progression in hemophilic men. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 19: 546-48. http://amedeo.com/lit.php?id=9859971 22. Schwarze-Zander C, Blackard JT, Zheng H, et al. GB virus C (GBV-C) infection in hepatitis C virus (HCV)/HIV-coinfected patients receiving HCV treatment: importance of the GBV-C genotype. J Infect Dis 2006; 194: 410-9. http://amedeo.com/lit.php?id=16845623 23. Sheng WH, Hung CC, Wu RJ, et al. Clinical impact of GB virus C viremia on patients with HIV type 1 infection in the era of highly active antiretroviral therapy. Clin Infect Dis 2007;44:584-90. Epub 2007 Jan 17. Abstract: http://amedeo.com/lit.php?id=17243064 24. Souza IE, Allen JB, Xiang J, et al. Effect of primer selection on estimates of GB virus C (GBV-C) prevalence and response to antiretroviral therapy for optimal testing for GBV-C viremia. J Clin Microbiol 2006;44:3105-13. Abstract: http://amedeo.com/lit.php?id=16954234 25. Souza IE, Zhang W, Diaz RS, Chaloner K, Klinzman D, Stapleton JT. Effect of GB virus C on response to antiretroviral therapy in HIV-infected Brazilians. HIV Med 2006;7:25-31. Abstract: http://amedeo.com/lit.php?id=16313289 26. Stark K, Doering CD, Bienzle U, et al. Risk and clearance of GB virus C/hepatitis G virus infection in homosexual men: A longitudinal study. J Med Virol 1999;59:303-6. http://amedeo.com/lit.php?id=10502260 27. Tillmann HL, Heiken H, Knapik-Botor A, et al. Infection with GB virus C and reduced mortality among HIV-infected patients. N Engl J Med,. 2001;345:715-24. http://amedeo.com/lit.php?id=11547740 28. Tillmann HL, Heringlake S, Trautwein C, et al. Antibodies against the GB virus C envelope 2 protein before liver transplantation protect against GB virus C de novo infection. Hepatology 1998: 28: 379-84. http://amedeo.com/lit.php?id=9696000 29. Tillmann HL, Manns MP, Claes C, Heiken H, Schmidt RE, Stoll M. GB virus C infection and quality of life in HIV-positive patients. AIDS Care 2004;16:736-43. http://amedeo.com/lit.php?id=15370061 30. Tillmann HL, Stoll M, Manns MP, Schmidt RE, Heiken H. Chemokine receptor polymorphisms and GB virus C status in HIV-positive patients. AIDS 2002;16:808-9. http://amedeo.com/lit.php?id=11964548 31. Tillmann HL, Kaiser T, Fox Z, et al. Impact of coinfection with HIV-1 and GB virus C in patients receiving a ritonavir-boosted HAART regimen: a substudy to the MaxCmin1 trial. J Acquir Immune Defic Syndr 2005;40:378-80. http://amedeo.com/lit.php?id=16249716 32. Toyoda H, Fukuda Y, Hayakawa T, et al. Effect of GB virus C/hepatitis G virus coinfection on the course of HIV infection in hemophilia patients in Japan. J Acquir Immune Defic Syndr Hum Retrovirol 1998;17:209-13. http://amedeo.com/lit.php?id=9495219 33. Yirrell DL, Wright E, Shafer LA, et al. Association between active GB virus-C (hepatitis G) infection and HIV-1 disease in Uganda. Int J STD AIDS 2007;18:244-9. Abstract: http://amedeo.com/lit.php?id=17509174 34. van der Bij AK, Kloosterboer N, Prins M, et al. GB virus C coinfection and HIV-1 disease progression: The Amsterdam Cohort Study. J Infect Dis 2005;191:678-85. http://amedeo.com/lit.php?id=15688280 35. Williams C, Allen J, Benning L, et al. Prevalence, acquisition, and clearance of GB virus type C in the women's interagency HIV study . Abstract, 12th CROI 2005, Boston.. http://www.retroconference.org/2005/cd/Abstracts/24123.htm 36. Williams CF, Klinzman D, Yamashita TE,E et al. Persistent GB virus C infection and survival in HIV-infected men. N Engl J Med 2004, 350:981-90. http://amedeo.com/lit.php?id=14999110 37. Xiang J, George SL, Wunschmann S, Chang Q, Klinzman D, Stapleton JT. Inhibition of HIV-1 replication by GB virus C infection through increases in RANTES, MIP-1alpha, MIP-1beta, and SDF-1. Lancet 2004, 363:2040-6. http://amedeo.com/lit.php?id=15207954 38. Xiang J, Sathar MA, McLinden JH, Klinzman D, Chang Q, Stapleton JT. South African GB virus C isolates: interactions between genotypes 1 and 5 isolates and HIV. J Infect Dis 2005;192:2147-51. Epub 2005 Nov 11. Abstract: http://amedeo.com/lit.php?id=16288381 39. Xiang J, Mc Linden J, Chang Q et al. Monoclonal antibodies directed against the GB Virus C major envelope glycoprotein neutralize HIV infectivity differentially in PBMC than in TZB-bl cells. 13th CROI 2006, Denver http://www.retroconference.org/2006/PDFs/417.pdf 40. Xiang J, McLinden JH, Chang Q, Kaufman TM, Stapleton JT. An 85-aa segment of the GB virus type C NS5A phosphoprotein inhibits HIV-1 replication in CD4+ Jurkat T cells. PNAS 2006, 103:15570-5. http://amedeo.com/lit.php?id=17030806 41. Xiang J, Wunschmann S, Diekema DJ et al. Effect of coinfection with GB virus C on survival among patients with HIV infection. N Engl J Med 2001;345:707-14. http://amedeo.com/lit.php?id=11547739 42. Yeo AE, Matsumoto A, Hisada M, Shih JW, Alter HJ, Goedert JJ. Effect of hepatitis G virus infection on progression of HIV infection in patients with hemophilia. Multicenter Hemophilia Cohort Study. Ann Intern Med 2000;132:959-63. http://amedeo.com/lit.php?id=10858179 43. Zhang W, Chaloner K, Tillmann HL, Williams CF, Stapleton JT. Effect of early and late GB virus C viraemia on survival of HIV-infected individuals: a meta-analysis. HIV Med 2006; 7: 173-80. http://amedeo.com/lit.php?id=1649463127