Towards an understanding of the side effects of anti-HIV drugs using Caenorhabditis elegans

Since the discovery of HIV-1 as a cause for AIDS, many antiretroviral drugs - such as the nucleoside reverse transcriptase inhibitors (NRTIs) and the protease inhibitors (PIs) - have been developed to target viral replication. The therapeutic use of a combination of drugs, more commonly known as Highly Active Anti-Retroviral Therapy (HAART), has significantly improved the quality and length of patient lives.
Overshadowing this success, however, is the problem that HIV-1 infected patients are afflicted with drug induced adverse events, some of which can be life threatening. Most adverse events seem to be related to tissues with high-energy demand and have predominantly been found to be caused by mitochondrial toxicity.
In this thesis the nematode Caenorhabditis elegans is used as a model system to study the adverse side effects of HIV-1 antiretroviral medicines administered alone or in combination. Using an array of established and novel molecular techniques, drugs that have similar chemical structure and modes of action are shown to each have distinct toxicity profiles. Evidence is shown in support of an earlier proposal that there are modes to NRTI toxicity beyond the polymerase-γ theory and a novel hypothesis that NRTIs cause premature and accelerated aging is assessed. Interestingly, the observed mitochondrial dysfunction and toxicity phenotypes of both NRTIs and PIs could be attenuated by antioxidants.
Taken together, this project has endeavoured to shed some light on the mechanisms behind HIV drug toxicity and ultimately benefit the development of new, effective, and less toxic compounds.