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Axel Fun

Tuesday 6 December 2011

Determinants of the Development and Evolution of HIV-1 Drug Resistance

Promotor: Prof.dr Emmanuel J.H.J. Wiertz
Defence: 19 January 2012

This thesis describes the contribution of different viral factors to the development and evolution of resistance to these drug classes. Although the factors are the same, the extent of their involvement is different for the individual antiretrovirals. An explanation for this comes from the observed differences in the genetic barrier to resistance. A single mutation is sufficient to fully overcome the drug pressure imposed by a CA/p2 maturation inhibitor (bevirimat) without much replication cost and consequently no further evolution is observed. One of the primary raltegravir resistance mutations confers relevant levels of resistance, probably around the clinical threshold but they substantially impair viral replication. In the majority of raltegravir resistance-associated virological failures secondary resistance mutations are selected to enhance resistance and restore the viral replication capacity. The genetic barrier of boosted PIs like lopinavir is higher than that of raltegravir, typically requiring >2-3 mutations to confer clinically relevant levels of resistance, with most resistance mutations negatively affecting viral replication. Resistance against these 2nd generation PIs, evolves in stepwise fashion with each individual mutations gradually increasing the resistance and/or improving overall viral fitness. This appears to be different for 3rd generation PIs like darunavir. In general, it requires even more mutations to overcome drug pressure and the contribution of the individual mutations is very small until a certain threshold is reached.
The collective viral and host factors control the shape and size of the viral population, which in combination with the potency and genetic barrier of the antiretroviral drug regimen ultimately determine if resistance variants will emerge or not.