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Antiretroviral drugs have made a significant impact on HIV/AIDS disease progression and have significantly extended the life expectancy of HIV-infected individuals, particularly when used in combination therapies such as HAART (highly active antiretroviral therapy). However, despite this success, recent reports indicate that HIV morbidity and mortality remain at epidemic proportions. It is estimated that over 33 million people are currently infected with the virus worldwide, while sub-Saharan Africa accounted for approximately 70% of all infected individuals and AIDS-related deaths in 2009 (UNAIDS, 2010). Issues of drug resistance, drug toxicity, correct patient compliance and the inability to remove latent reservoirs of infection remain significant problems to overcome. The need to develop novel and improved therapeutic strategies against HIV therefore remains an important medical objective. Gene-based therapies hold much promise as alternative treatment strategies for HIV/AIDS. Anti-viral gene therapies aim to provide a once-off, long-lasting treatment against the virus and thereby address some of the shortcomings associated with current antiretroviral therapies. A gene therapy against HIV offers several unique advantages, including the sustained inhibition of viral replication and the removal of virus from cellular reservoirs. Moreover, by improving specificity, the common toxic side effects associated with current antiretrovial regimens can be diminished. A number of different RNA-based and protein-based gene therapy strategies have been explored and some have reached phase 1 and 2 clinical trials. Our research focuses on the development of RNA-based antiviral strategies and in particular, those that utilise gene expression strategies based on RNA interference (RNAi). In this chapter, we examine basic concepts and review recent advances in the development of expressed RNAibased systems against HIV, with a focus on progress in construct and target design. We also discuss topics related to the use of RNAi-based strategies, including appropriate construct expression, target specificity, viral escape mutations and effective construct delivery. We aim to identify desirable properties of an RNAi-based anti-HIV therapy and highlight the future developments that are required to make this approach a reality.

RNAi-Based Gene Expression Strategies to Combat HIV