The prognosis of those infected with HIV-1 has improved significantly since the introduction of highly active antiretroviral therapy (HAART). This has led to complete suppression of HIV-1 replication and reduction of viraemia to undetectable levels. Initially HAART comprised of three classes of drugs, namely nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs), which target two important viral enzymes. Until recently, patients developing highly drug-resistant HIV-1 have had limited therapy options. This has changed in the last few years with the development and approval for use of second-generation NNRTIs and PIs, and three new classes of drugs including integrase strand transfer inhibitors (INSTIs). This means that patients undergoing INSTI-containing salvage therapy are taking drugs targeting all three HIV-1 pol genes; protease (PR), RT and IN. However, little data is available on the evolution, interaction and linkage of drug resistance mutations throughout the pol gene. In this study, we developed a single genome sequencing assay of the full-length HIV-1 pol gene and used it to investigate the development and linkage of drug resistance mutations in sequential samples from two patients failing INSTI-containing salvage therapy. Different phylogenetic methods were used to explore the evolution and dynamics of drug resistance mutations in the full-length HIV-1 pol gene. Furthermore, we examined the effect of co-evolved PR and RT on the susceptibility of patient-derived viruses to INSTIs and viral replicative fitness. Our data indicate that the development of drug resistance mutations in IN is complex and is a fine balance between attaining high levels of drug resistance and decent replicative fitness. This is to a degree influenced by mutations in other regions of the HIV-1 pol gene. Taken together, the data suggests that larger regions of patient-derived HIV-1 genome should be examined in order to get a good understanding of HIV-1 drug susceptibility.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:626429 |
| Date | January 2013 |
| Creators | Martin, A. S. |
| Contributors | Pillay, D. ; Mbisa, J. L. ; Cane, P. A. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1413952/ |
Page generated in 0.0109 seconds