RNAi as an antiviral therapy

Abstract

There are a dozen or so viruses that will continue to be a serious global health threat for many years to come, mainly due to their chronic nature. These include hepatitis C virus (HCV), human papillomavirus viruses (HPVs), West Nile virus and human herpes viruses (i.e., HSV, CMV, EBV, HHV-8, etc.). However, HIV-1 infections will remain at the top of the list due to its high prevalence and the significant mortality and morbidity from AIDS. The development of a suitable vaccine against HIV-1 remains an important area of public interest. The initial hope of identifying the specific anti-HIV-1 antigenic epitopes that can protect HIV-1-infected individuals and serve as a potential vaccine has been replaced by the realisation that we have yet to identify a clear correlation of protective immunity against HIV-1 infection. Understanding the anti-HIV-1 protective factors and their potential role in the development of a vaccine or inexpensive therapy remains one of the major obstacles in HIV-1 research. In the last quarter century – since the realisation of AIDS – previous studies have established that the role of humoral or cellular immune responses in protecting human hosts against HIV-1 have been inconclusive. Moreover, most of the publicised and awaited clinical trials on vaccines have failed. The recent discovery of RNA interference (RNAi) has raised the possibility of developing a new generation of vaccines that can stymie human viruses, particularly HIV-1 replication at various stages of its life cycle at the intracellular level. Various transcripts in the HIV-1 life cycle can be targeted, and specific small double-stranded RNAs (small interfering RNAs) can be developed against these HIV-1-specific targets. However, some recent data suggests that RNAi-based therapeutics against this virus should be viewed with strong caution. Specifically, there are multiple factors that make HIV-1 a difficult infection to ‘cure’ because of HIV-1 latency. The changing nature of HIV-1 genomes and the possible presence of microRNAs within the HIV-1 genes can suppress RNAi directed against HIV-1 gene targets. Thus, HIV-1 would be a difficult epidemic to overcome by RNAi-based therapeutics.

Keywords::

• Dicer
• double-stranded RNA
• endogenous mRNA
• HIV-1
• latency
• lentivirus
• long-term survivors
• microRNA
• retroelements
• retrotransposons
• retroviruses
• RNA-dependent RNA polymerase
• RNA interference
• small interfering RNA
• transposons
• zoonosis