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.
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