HCMV protein kinase and DNA polymerase domains involved in antiviral sensitivity, viral replication and cell tropism [ 2004 - 2006 ]

Research Grant

Researchers: Prof William Rawlinson (Principal investigator) ,  Dr Gillian Scott

Brief description 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.

Funding Amount $AUD 269,250.00

Funding Scheme NHMRC Project Grants

Notes Standard Project Grant