HIV cure continues to be elusive due to cellular reservoirs that persist despite the highly potent combined antiretroviral therapy (cART) which suppresses HIV plasma viremia to undetectable levels. One of the cure strategies currently being pursued is "Shock-and-Kill", which uses latency reversing agents (LRAs) to activate provirus expression in the presence of cART to avoid reservoir reseeding, while exposing the virus-expressing cells to immune responses for eradication. To date, there is no licensed LRA due to their limited clinical success, i.e., their failure to consistently and significantly reduce the viral reservoir in human clinical studies. New LRAs and LRA combinations are therefore likely needed for the shock-and-kill approach to succeed. Natural products are a rich repository for novel antivirals and latency modulating agents. My thesis documents and provides molecular analysis of African medicinal plants and naturally-produced chemical compounds that modulate latent HIV-1 infection. First, to highlight the therapeutic potential of naturally-produced chemical compounds, 19 African medicinal plants, whose anti-HIV or latency modulating properties have been documented and are supported by detailed laboratory data in the literature, are discussed in a systematic review (Chapter 2). Furthermore, this thesis, which is interdisciplinary in character, features an exploratory community-based project, involving 13 Traditional Health Practitioners (THPs). This ethnopharmacological study documented 83 medicinal plants used for HIV/AIDS and related diseases management by the BaKalanga Peoples of the Tutume-sub district in Central Botswana. Thirty-eight (45.8%) of the identified medicinal plants have not been previously investigated for HIV-1 specific bioactivities linked to their ethnomedicine use reported in our survey and therefore should be prioritized for bioassay-based studies in the future, in the search for more novel antivirals and LRAs. Finally, this thesis identifies and characterize five (5) novel latency modulating compounds derived from natural sources namely: psammaplin A; aplysiatoxin; debromoaplysiatoxin; knipholone anthrone (KA) and its analogue anthralin (dithranol). Taken together, my thesis supports the search for novel HIV-1 latency modulating agents and indeed antivirals from natural products to improve "shock-and-kill"-based therapies and eventually finding a cure for HIV.
Copyright is held by the author(s).
This thesis may be printed or downloaded for non-commercial research and scholarly purposes.
Supervisor or Senior Supervisor
Thesis advisor: Brockman, Mark
Member of collection