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Schönewolf, Nicola (2010): Mutationen in der Connection und RNAse H-Domain der Reversen Transkriptase von HIV-1. Dissertation, LMU München: Faculty of Medicine
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Abstract

HIV-1 reverse transcriptase (RT) polymerase domain is known as target of nonnucleoside (NNRTIs) and nucleoside (NRTIs) reverse transcriptase inhibitors. However, resistance mutations in the polymerase domain lead repeatedly to therapeutic failure. The Connection (CN) and RNAse H domains of HIV-1 RT have recently gained more interest. They also might serve as independent new drug targets. Recently, in several in vitro studies several mutations in the CN and RNAse H domains were suggested to interfer with Polymerase resistance mutations (TAMs or finger domain mutations). In our in vivo approach, a clear differentiation between different HIV-1 subtypes was performed. Sequences of 57 HIV-1 subtype B infected patients were analysed. Their mutation status in the Connection and RNAse H domains was compared to a subtype-specific reference sequence. The sequences were studied for mutations. A potential correlation to Polymerase domain resistance mutation was analysed. Highly conserved amino acids and a number of natural polymorphisms were found for most of the studied positions. Subtype specific amino acid patterns were found. However, for positions 333, 359, 371, 390 and 558 a significant correlation to Polymerase domain resistance mutations was found. In conclusion, five positions were detected that might be involved in resistance mechanisms. The creation of a subtype specific reference sequence was necessary in order to distinguish between drug related mutations, subtype specific conservation or natural polymorphism. Extended sequence analysis to these regions are not recommended due to the small number of mutations found. Subtype speficication is highly recommended in order to gain resilient data.