HCMV protein kinase and DNA polymerase domains involved in antiviral sensitivity, viral replication and cell tropism

Funding Activity

Website
http://purl.org/au-research/grants/nhmrc/300532

Funding Status
Closed

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Funded Activity Summary

Many individuals with compromised immune systems - such as those with HIV-AIDS, cancer and transplant recipients are at risk of disease from human cytomegalovirus (HCMV) infection. Currently the most effective therapies are suppression of virus replication by continuing administration of antiviral agents, principally ganciclovir (GCV), cidofovir (CDV) or foscarnet (phosphonoformic acid or PFA). The use of antivirals for increasingly longer durations in an enlarging population of patients with irreversible chronic immunosuppression, has resulted in the emergence of increasing numbers of drug-resistant HCMV viruses in this group of individuals. In patients with AIDS, 7.6% of isolates in one study were shown to be GCV resistant and we have found similar levels (10.8%) in immunosuppressed Australians. Of the small number of antiviral agents with any useful activity against HCMV, GCV, and aciclovir (ACV) are nucleoside analogues. PFA is a pyrophosphate analogue that competitively inhibits pyrophosphate binding by HCMV DNA polymerase. These drugs are activated by a specific gene of HCMV (UL97 (Pk)) and a mouse virus (MCMV - M97Pk) that is very similar to HCMV. The drug then acts on a second gene encoding the DNA polymerase (HCMV UL54 DP or MCMV M54DP) to prevent viral growth. We are investigating the resistance genotypes and phenotypes in CMV resistant to 7 antiviral drugs including GCV, CDV and PFA. We have shown new resistant genotypes and are currently determining the protein-functional correlates of the genotypic changes, in order to increase understanding of the PK and DP genes, define the genetic causes of resistance, and to produce better targets for antiviral agents.

Funded Activity Details

Start Date: 01-01-2004

End Date: 01-01-2006

Funding Scheme: NHMRC Project Grants

Funding Amount: $269,250.00

Funder: National Health and Medical Research Council

Research Topics

ANZSRC Field of Research (FoR)

Applied immunology (incl. antibody engineering xenotransplantation and t-cell therapies)

ANZSRC Socio-Economic Objective (SEO)

There are no SEO codes available for this funding activity

Other Keywords

antiviral | antiviral therapy | biochemistry and molecular biology | cytomegalovirus | gene structure / protein function / novel therapies | infection disease | molecular genetics | murine models | viral infection | virology

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