| The treatment of human immunodeficiency virus (HIV) is expanding to developing countries, where non-B subtypes are responsible for the HIV epidemic. In order to better understand how drug resistance may impact viral replication, we sought to determine the fitness costs of thymidine analog mutations (TAMs) and non-nucleoside Reverse Transcriptase (RT) inhibitor (NNRTI) resistance mutations in subtype B and C HIV.;Subtype B and C HIV act differently in the presence of TAMs, and these differences may lead to increased transmitted resistance in a subtype C setting. The 67N and 70R accessory mutations created an RT that was more fit than the wild type RT in the subtype C RT, but in subtype B these mutations had a similar replication capacity as the wild type. In addition, the TAM-1 triple mutant, 41L/210W/215Y, replicated as well as the wild type in subtype C, whereas in subtype B the mutant was less fit than the wild type.;The response to NNRTI resistance mutations differs between subtype B and C as well, however the replication impacts can also vary within a subtype. The 106A and 106M mutations produced weak viruses in the consensus subtype C RT, while the subtype B RT tolerated the mutations well. When testing the mutations in another subtype C RT, not only were the 106A and 106M mutants non-viable, but the 188C and 190A mutants would not grow either.;The fitness impacts of drug resistance mutations depend on the sequence background of RT as illustrated in an additional RT sequence cloned from a patient infected with subtype C HIV and failing highly active anti-retroviral therapy. This patient had the TAM-2 pathway resistance mutations of 67N/70R/215F/219Q and two NNRTI resistance mutations, 103N and 106M at the time of virological failure. When the multi-drug resistant mutant was compared to the TAM-1 mutant, there was no fitness difference between the two RTs. However, when the NNRTI resistance mutations were removed, the TAM-1 mutant was able to out-compete the TAM-2 mutant. In conclusion, this dissertation suggests that drug resistance mutation fitness impacts differ not only between subtypes but in an RT sequence-specific manner. |
