HIV-1 drug resistance and investigation of Tetherin-Vpu as a potential therapeutic target.
Doctoral thesis, UCL (University College London).
The Red Queen hypothesis elegantly reflects virus-host interactions whereby alternate switching in selective advantage occurs between host and parasite. HIV has a prolific ability to generate genetic diversity, contributing to viral persistence. This property presents serious challenges to sustained treatment with antiviral drugs on a global scale. In resource poor settings where viral monitoring is not currently feasible, the possibility of more widespread resistance exists. In this thesis I demonstrate using meta-analysis that lack of viral load monitoring in the first year of antiretroviral treatment is associated with higher prevalence of resistance in patients with viral failure. A second meta-analysis suggests that use of boosted protease inhibitors as first line therapy is associated with lower prevalence of resistance mutations compared to non-nucleoside reverse transcriptase inhibitors, therefore potentially limiting the emergence of resistant HIV strains. The use of Pis in such areas might, however, be complicated by our findings that certain viruses circulating in resource poor regions (not previously exposed to PIs) have reduced PI susceptibility due to gag polymorphism, highlighting the plasticity of HIV. The continual evolution of drug resistance means that further research into alternative targets is required. Such targets may include host factor-virus interactions. The mammalian restriction factor BST-2/tetherin is counteracted by HIV-1 using its Vpu protein. We show that tetherin has been under positive selection in primates. Furthermore tetherin can be rendered almost insensitive to Vpu by a single positively selected substitution, revealing this as a potentially important drug target, and suggesting tetherin's evolution has been shaped by viruses. Intriguingly, most SIV do not encode Vpu, and I show that the envelope protein of SIVtan is able to counteract tetherin by intracellular sequestration. Pharmacological blockade of Vpu-tetherin interactions should be investigated, although we have highlighted a potential mechanism for virus escape through gain of function by envelope.
|Title:||HIV-1 drug resistance and investigation of Tetherin-Vpu as a potential therapeutic target|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Infection and Immunity (Division of)|
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