Valganciclovir and Human Herpesvirus-8

Valganciclovir and Human Herpesvirus-8

All eight human herpesviruses have a conserved herpesvirus protein kinase (CHPK) that is important for the lytic phase of the viral life cycle. Corey et al. A total of 12 well-characterized GCV-sensitive or -resistant strains and clinical isolates were used. Many studies have reported that at least some of the drug-resistant herpesviruses retain their pathogenicity and can be associated with progressive or relapsing disease. Analysis of virus mutants in animal models and in patient populations can help assess the value of viral proteins such as the HSV thymidine kinase and ribonucleotide reductase as drug targets and the pathogenic potential of drug resistant mutants. Following primary infection, KSHV establishes latent infection in the host cell, with only a small population of cells undergoing spontaneous lytic reactivation (8, 9). In recent years, the resistance of CMV to antiviral drugs has been extensively reviewed.

A ganciclovirresistant mutation results in a UL97 protein that is unable to phosphorylate ganciclovir. Mollusca is the second-most-diverse phylum, with nearly 85,000 described species (1, 2) and a total world estimate of 120,000 to 200,000 species (3). By attaching a valine ester to ganciclovir (valganciclovir), the bioavailability of the orally administered drug is greatly increased to 68% [5]. A valine esterase in the human gastrointestinal mucosa cleaves the valine and results in ganciclovir in the portal blood circulation. Therapy is further complicated by viral latency, ie, the ability of the virus to incorporate its genome in the host genome, with clinical infection becoming evident without reexposure to the organism. The article by Casper et al. Each viral latent protein plays an important role in viral pathogenesis and KSHV-associated tumorigenesis.

Valganciclovir and Human Herpesvirus-8
Ganciclovir has been shown to be phosphorylated in the presence of both the HHV-8 thymidine kinase (open reading frame [ORF] 21) and the HHV-8 phosphotransferase (ORF36) [7]. Two other reports, however, provide conflicting evidence, which suggests that the thymidine kinase of HHV-8 does not phosphorylate ganciclovir [8, 9]. It is not completely clear, therefore, how ganciclovir is activated to ganciclovir triphosphate during HHV-8 infection. Phosphorylation by a cellular enzyme remains a possibility. It has also been shown that ganciclovir, cidofovir, and foscarnet inhibit the production of HHV-8 from latently infected cell lines upon stimulation, whereas acyclovir has little or no activity [10–12]. The possibility that ganciclovir or valganciclovir might inhibit HHV-8 replication and prevent development of Kaposi sarcoma in HIV-infected patients was suggested by the observation that patients who received 4.5 g daily of orally administered ganciclovir to prevent development of CMV retinitis in the eye without an ocular ganciclovir implant also had a lower incidence of Kaposi sarcoma in a large clinical trial [13]. This suggested the intriguing possibility that replicating HHV-8 expressed lytic proteins or stimulated cellular cytokines, which contributed to the development of Kaposi sarcoma.

It has been suggested that in KS lesions, the lytic cycle gene products may be involved in proliferation of neighboring cells, contributing to pathogenesis [14]. One attractive candidate is an early lytic protein of HHV-8 that might contribute to oncogenesis is the viral-encoded G-protein- coupled receptor of HHV-8 (ORF74) [15]. This protein has been shown to be a viral oncogene and angiogenesis activator. The expression of ORF74 induces an angiogenesis phenotype by secretion of vascular endothelial growth factor, an angiogenesis growth factor. Drugs were purchased from LKT Laboratories (PCV; St Paul, MN), Sigma Chemical Company (ACV, AraA, BrdU, BVdU, EDU, GCV, and IUdR; St Louis, MO), and Gemini Biologicals (CDV, GCV; West Sacramento, CA) or were synthesized by GLSynthesis (EDU, HBPG, and TFT; Worchester, MA). Another viral protein that may be a candidate for contributing to pathogenesis is the HHV-8 homologue of human IL-6, the vIL-6 protein. Thus, prevention of HHV-8 replication might provide therapeutic benefits in human disease.

This study by Casper et al. [6] provides evidence that valganciclovir is the first antiviral agent that has been shown to reduce HHV-8 replication in a randomized clinical trial. The study design was a double blind, placebo-controlled crossover trial in which 26 HHV-8 infected men were randomized to receive 8 weeks of valganciclovir or placebo (900 mg once per day administered orally). The idea is that such viral proteins would be excellent drug targets because drug-sensitive viruses would interfere with the replication of drug-resistant variants. Oral swab samples were taken daily and analyzed for HHV-8 DNA and CMV DNA by real time PCR . Sixteen HIV-positive men and 10 HIV-negative men completed the study. 1A) and its southern counterpart, (South)-methanocarbathymidine (S-MCT), which contains the pseudosugar ring locked in the southern conformation, were synthesized as previously described (37).

The antiviral effect of valganciclovir reduced the frequency and quantity of HHV-8 that was detected in the oropharynx; this effect was prompt and occurred independently of the reduction in CMV replication. The Casper et al. [6] study also provided evidence that HHV-8 replication occurs independently of CMV replication in immunocompromised patients. The hematologic, renal, and hepatic toxicities of valganciclovir were similar to those of placebo in this short trial of low-dose valganciclovir. The Casper et al. [6] study provides important new quantitative data that valganciclovir suppresses replication and oropharyngeal shedding of HHV-8 and sets the stage for additional research to determine whether valganciclovir prevents Kaposi sarcoma in patients at high risk due to immunosuppression. It has also shown excellent activity in animal studies (Bidanset 2004, Quenelle 2004).

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