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Therapy for HDV!
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John M. Taylor, Ph.D.
Fox Chase Cancer Center, Philadelphia, PA
Hepatology, December 2003, Volume 38, Number 6
Hepatitis delta virus (HDV) can dramatically worsen liver disease in patients coinfected with hepatitis B virus (HBV). No effective medical therapy exists for HDV. The HDV envelope requires HBV surface antigen proteins provided by HBV. Once inside a cell, however, HDV can replicate its genome in the absence of any HBV gene products. In vitro, HDV virion assembly is critically dependent on prenyl lipid modification, or prenylation, of its nucleocapsid-like protein large delta antigen. To overcome limitations of current animal models and to test the hypothesis that pharmacologic prenylation inhibition can prevent the production of HDV virions in vivo, we established a convenient mouse-based model of HDV infection capable of yielding viremia. Such mice were then treated with the prenylation inhibitors FTI-277 and FTI-2153. Both agents were highly effective at clearing HDV viremia. As expected, HDV inhibition exhibited duration-of-treatment dependence. These results provide the first preclinical data supporting the in vivo efficacy of prenylation inhibition as a novel antiviral therapy with potential application to HDV and a wide variety of other viruses. (In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus; J. Clin. Invest. 112:407-414 (2003); Bruno B. Bordier, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California, USA, Veterans Administration Medical Center, Palo Alto, California, USA)
The above study was recently published along with a helpful associated commentary by Heller and Hoofnagle. Hepatitis delta virus (HDV) is a subviral RNA satellite whose replication cycle depends on envelope proteins provided by its natural helper virus, hepatitis B virus (HBV). Some time ago Glenn et al. found that the large delta protein not only could be isoprenylated but indeed had to be isoprenlyated in order to fulfil its function as a facilitator of HDV particle assembly. For some time they have suggested that an inhibitor of isoprenylation might function to block HDV assembly and become part of a therapy for HDV infections. In 1998 and 2002 they reported inhibition of HDV assembly from transfected cultured cells using prenylation inhibitors.
The present report by Bordier et al. brings together several previous components. (1) It makes use of the concept of mice that are transgenic for the expression of HBV in the liver, a strategy first used by Guidotti et al. (2) It makes use of hydrodynamic transfection of mice with HDV cDNA sequences as a way to initiate HDV genome replication. This was first achieved by Chang et al. (3) Hydrodynamic transfection is a surprising technology first developed by Liu et al. Not surprisingly, when HDV genome replication is thus initiated in the liver of HBV transgenic mice, HDV RNA containing particles are released and can be detected in the blood of the mouse. These virus particles will have little if any ability to infect other hepatocytes. And, the expression of the HDV genome becomes undetectable after 2 to 3 weeks. (4) To this picture the investigators then bring to bear the use of two drugs known from other studies to block the isoprenylation process. These drugs have been developed separately and are apparently now in phase I/II trials. They are being applied because of their ability to block a post-translational isoprenylation that is required for the oncogenic properties of the Ras oncogene; there is thus hope that such treatments will even be able to inhibit activated Ras associated with certain human tumors. As mentioned above, the present investigators have already reported that such inhibitors will act on the assembly of HDV from cultured cells. Therefore, it is not too surprising that in the present report, the investigators were able to treat mice with the inhibitors and suppress HDV assembly.
With this experimental mouse model the authors were pleased to observe serum titers of at least 107 HDV genome equivalents per milliliter. They even cite unpublished studies in which the titer was 10-fold higher. What was striking was the high level of inhibition they achieved with the prenylation inhibitors; based on RT-PCR assays the virus titers dropped at least 1,000-fold after 7 days of treatment. Objectively, the investigators did not show that isoprenylation of the large delta protein or of host proteins was blocked within the liver of the treated mice. They did not monitor whether the release of HBV surface antigen was changed. A recent study has shown that lovastatin, a drug that interferes with cholesterol synthesis, can interfere with HBV particle (and hence HDV) assembly.
The investigators admit that the “inhibition exhibited duration-of-treatment dependence.” In addition, the treatment did not reduce the level of HDV accumulation in hepatocytes. Therefore, they are still a long way from what they propose as a therapeutic treatment for patients infected with HDV. Even in their model system, it should be noted that they are studying a transient transfection and have not mimicked a chronic HDV infection. Independent of the given reasons to the contrary, the investigators need to test the inhibitors in a woodchuck chronically infected with woodchuck hepatitis virus and HDV.
In treatments of patients with chronic HBV/HDV we might expect the use of therapies against the helper virus, HBV, to be more valuable. However, there is a puzzling report that such treatments did not lower HDV RNA levels in patients chronically infected with HDV. Of course, a combined therapy might be better.
In their abstract the investigators refer to the potential for this treatment to be relevant to “a wide variety of other animal viruses.” Presumably this refers to a prediction made by the investigators long ago, that some animal virus proteins, other than the HDV large antigen, contain C-terminal domains that might allow isoprenylation. Additional studies need to be carried out to test such speculations.
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