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HIV treatment and research on natural products
The antiretroviral agents which are currently available for the treatment of HIV infection targets enzymes essential to the life cycle of the virus. HIV reverse transcriptase (RT) is crucial for viral replication, HIV protease facilitates maturation and infectivity of virion particles and HIV intergrase mediates HIV intergration into the host genetic material (Ng et al., 1997).
More than twenty drugs have already been licensed for HIV treatment, including formulations of both individual and combined antiretroviral agents.
Specific inhibitors of several stages of the viral cycle, including viral attachment and entry are subject to preclinical investigation or have already entered clinical trials (Notka et al., 2003). Efforts to find other anti-HIV agents have been mainly focused on the development of drugs that targets viral proteins, which are essential for viral replication. The current antiviral therapy presents important limitations such as side effects and appearance of mutant viruses that are resistant and makes drugs which are currently in use to be insufficient to maintain a safe theraupeutic arsenal against HIV (Bedoya et al., 2006; Ma et al., 2002).
There is a global need or demand for broader, safer and cheaper drugs for the treatment of HIV infection. One of the approaches is to find anti-HIV agents from medicinal plants. New anti-HIV compounds from natural sources are often reported, some are essentially unproven and others with distinct promise based on in vitro research. Natural products have been a consistently successful source in drug discovery and may offer more opportunities to find anti-HIV drugs or lead compounds (Wang et al., 2006). A number of medicinal plants have been screened and resulted in the isolation of some active compounds with inhibitory activity on HIV. One of the most promising anti-HIV compounds, calanolide was isolated from a Malaysian tree belonging to the Garcinia family. Calanolide, a coumarin, is now being tested in human trials (Gurib-Fakim, 2006). Other coumarins with anti-HIV activity have been reported by Bedoya et al. (2005) and Uchiumi et al. (2003). Active compounds like benzo[c]phenanthridine decarine and others isolated from Zanthoxylum ailanthoides (Figure 1.4) also showed anti-HIV activity in acutely infected H9 cells as reported by Cheng et al. (2005).
Nuclear factor kappa B (NF-kB) and viral Tat transactivator
NF-kB constitutes a family of transcription factors that is important for cellular functions such as cell cycle progression and proliferation (Akesson et al., 2003). It plays an important role in the regulation of a multitude of genes (Figure 1.6) involved in cell survival and it has also been implicated in inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, asthma and atherosclerosis. When cells are not stimulated, NF-kB is retained in the cytoplasm in a complex with the inhibitor of kB (lkB) proteins. NF-kB can be activated by stimuli including pro-inflammatory cytokines TNF-µ which promotes phosphorylation of the IkB proteins followed by degradation of lkB and subsequent translocation of NF-kB into the nucleus (Lindgren et al., 2001).
The Tat protein of HIV-1 is a small polypeptide of 101 amino acid essential for the transcription of viral genes and for viral replication. Tat activates HIV-1 transcription by promoting the assembly of transcriptionally active complexes at the LTR through interaction with TAR (Figure 1.7). Upon transcriptional activation, multiple spliced, short transcripts arise, encoding for viral accessory proteins including Tat and Rev. These accessory proteins enhance viral transcription and promote the expression and export of the late, unspliced RNAs from the nucleus (Marcello et al., 2004).
Chapter 1: Introduction
1.1 Background
1.2 HIV/AIDS
1.3 Aims and objectives and objectives of the study
1.4 Plant selection
1.5 Scope of thesis
1.6 Hypothesis
1.7 References
Chapter 2: Activity of crude extracts against glycohydrolase and reverse transcriptase enzymes
2.1 Introduction
2.2 Material and methods
2.3 Results and discussion
2.4 References
Chapter 3: NF-kB, Hela-Tat and cytotoxicity assays on plant extracts
3.1 Introduction
3.2 Materials and methods
3.3 Results and discussion
3.4 References
Chapter 4: Isolation of compounds from Elaeodendron transvaalense extracts
4.1 Introduction
4.2 Materials and methods
4.3 Results and discussion
4.4 References
Chapter 5: Anti-HIV activity of compounds isolated from Elaeodendron transvaalense
5.1 Introduction
5.2 Materials and methods
5.3 Results and discussion
5.4 References
Chapter 6: Cytotoxicity of Elaeodendron transvaalense extract and isolated compounds
6.1 Introduction
6.2 Materials and methods
6.3 Results and discussion
6.4 References
Chapter 7: General discussion and conclusions
7.1 Introduction
7.2 Activity of crude extracts against reverse transcriptase and glycohydrolase enzymes
7.3 NF-kB, Hela-Tat and cytotoxicity assays on plant extract
7.4 Isolation of compounds from Elaeodendron transvaalense extract
7.5 Anti-HIV activity of pure compounds isolated from Elaeodendron transvaalense
7.6 Cytotoxicity of Elaeodendron transvaalense extract and isolated compounds
7.7 Conclusion
