Tachedjian Group

Retroviral Biology and Antivirals

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Overview

Our overall goal is to develop effective drug-based strategies to prevent viral infections such as the sexual transmission of HIV in women.

We achieve this through translational studies to discover, develop and elucidate the mechanism of action of novel antivirals for HIV prevention and by understanding the impact of intrinsic factors present at the vaginal mucosa on HIV and other sexually transmitted infections that promote HIV transmission.

We undertake fundamental studies to understand the biology of retroviruses including the interactions between viral and host cell factors. The aim is to translate these findings into the discovery of new drug targets for antiretroviral therapy and prevention.

Objectives

  • To develop a novel class of HIV reverse transcriptase inhibitor for HIV prevention and exploit these molecules to study enzyme function
  • To understand the mechanism of action of dendrimer nanoparticles against HIV
  • To perform preclinical evaluation of antiviral agents including microbicides
  • To understand the role of drug resistance mutations selected during antiretroviral therapy
  • To determine how intrinsic vaginal factors affect the transmission of HIV and other sexually transmitted infections
  • To understand virus-host interactions

Highlights

  • Discovery of small chemical building blocks (fragments) with mechanism of action distinct to HIV reverse transcriptase inhibitors used in the clinic
  • Discovery of a vaginal microbiota metabolite, lactic acid, that is more potent than acidity alone in killing HIV-1
  • Identification and characterisation of endogenous retroviruses in bats
  • Structure-activity relationship studies of dendrimer microbicides against HIV and genital herpes revealing that the dendrimer SPL7013 is the most potent against both viruses
  • Successful completion of a phase I dendrimer microbicide, SPL7013 Gel (VivaGel) clinical trial in healthy women demonstrating retention of HIV-1 and HSV-2 inhibitory activity.
  • Discovery of a novel mutation, N348I in the C-terminal domain of the HIV reverse transcriptase which confers resistance to zidovudine and nevirapine
  • Demonstration that potent members of a class of HIV-1 drugs called non-nucleoside reverse transcriptase inhibitors block the production of viral particles by increasing the processing of viral polyproteins inside the host cell
  • Discovery of small chemical building blocks (fragments) with mechanism of action distinct to HIV reverse transcriptase inhibitors used in the clinic

Projects