Kletenkov, Konstantin. The role of the HIV-1 protease substrate in therapy resistance. 2015, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_11556
HIV resistance against PIs is typically characterized by the accumulation of structural alterations in the viral protease (PR). However, a number of cases of clinical therapy failure under PI-containing regimes have been reported, where genotypic resistance testing did not reveal sufficient explanation from information on the PR and regimen compliance [5, 6]. And certain alterations in the natural substrate of the PR, Gag polyprotein, have been associated with the development of PI resistance [7-13]. Nevertheless, until today most algorithms evaluating PI resistances take solely the protease gene itself into account.
In the SHCS protease inhibitor use and successful treatment are monitored regularly for all patients and every newly enrolled patient receives a genotypic resistance test. We used in vivo cross-sectional sequence data from SHCS patients to scrutinize PI resistance mutational pathways across Gag and PR. Roles of certain mutations as well as of their interactions were investigated.
Here we demonstrate that roughly every fifth of the SHCS patients carries resistance mutations in Gag. And since Gag is not considered by the current genotyping systems the overall level of PI resistance for these patients is underestimated. We report novel Gag mutations of potential clinical relevance and provide additional details on known resistance mutational patterns. Additionally our data support a new potential role of p6 alterations in PI resistance mediated by its phosphorylation. Taken together, our results suggest the relevance of Gag sequence information for the routine genotyping of PI-treated patients of the SHCS.
|Advisors:||Affolter, Markus and Klimkait, Thomas and Gosert, Rainer|
|Faculties and Departments:||05 Faculty of Science > Departement Biozentrum > Growth & Development > Cell Biology (Affolter)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||1 Online-Ressource|
|Last Modified:||30 Jun 2016 10:59|
|Deposited On:||26 Feb 2016 09:11|
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