A thesis submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Doctor of Philosophy. August 2014. / Human immunodeficiency virus (HIV), the causative agent of the acquired
immunodeficiency syndrome (AIDS), remains a topic of global concern even though great
strides have been made to combat the virus. The high replicative rate of the virus and
recombination of the variety of viral strains complicate the treatment of AIDS. There has
been an increasing prevalence of African HIV strains in the Americas and Europe. The viral
protease (PR) is vital for the propagation of the virus; and thus, is a major target in antiviral
therapy. The HIV-1 PR enzyme from the subtype C strain; which predominates in sub-
Saharan Africa, has been greatly under-investigated in comparison to the protease from the
subtype B strain which predominates in North America and Europe. Enzyme activity data
which were part of this work suggested that the South African HIV-1 subtype C protease (CSA
PR) displays improved substrate turnover in comparison to the subtype B PR.
Thermodynamics and inhibition kinetics of drug binding showed that the C-SA PR is less
susceptible to certain clinically-used protease inhibitors when compared to the subtype B PR.
A crystal structure of the C-SA PR was solved and showed no difference to the global
structure of the subtype B PR. Molecular dynamics simulations showed that the C-SA PR
exhibits a wider range of open conformations. Hydrogen/deuterium exchange-mass
spectrometry (HDX-MS) was performed to elucidate the mechanism of reduced drug
susceptibility displayed by the C-SA PR. HDX-MS data provided insights into the basis of
the increased preference for open conformers displayed by the C-SA PR and the stability of
the terminal dimer interface which is a target in protease inhibition.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/16922 |
| Date | 06 February 2015 |
| Creators | Naicker, Previn |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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