Tesis doctoral de María José Buzón Gómez
Raltegravir is the first in-class hiv-1 integrase inhibitor approved for the treatment of hiv-1 infected subjects. However, like all other hiv inhibitors, the emergence of drug resistance limits its clinical efficacy. understanding the differential prevalence rate of mutations within the integrase coding region from highly active antiretroviral therapy (haart)-experienced but integrase inhibitor naí¯ve subjects could help identify whether clinically relevant viral mutations or natural polymorphisms occur, and whether the sequence diversity of the integrase gene has important implications in the clinical response to integrase inhibitors. Therefore, the first objective of this project thesis was to explore intrasubject longitudinal evolution of the hiv-1 integrase-coding region over a median of 10 years of heavy antiretroviral therapy in integrase inhibitor naí¯ve subjects. An additional objective was to explore changes in phenotypic susceptibility to raltegravir and replication capacity in those samples that accumulated the highest number of amino acid substitutions during the study period. Our results showed that hiv-1 integrase from longitudinal samples did not show evidence of genotypic or phenotypic resistance to raltegravir. Long-term antiretroviral pressure did not impair the raltegravir susceptibility and appeared to drive the replication capacity of integrase-recombinant viruses towards improved phenotypes, suggesting no fitness cost associated with long-term treatment. Therefore, our data suggest that current antiretroviral regimens do not diminish the fitness of integrase or influence raltegravir efficacy. no studies have evaluated the potential phenotypic contributions of mutations outside the integrase coding region in subjects whose raltegravir-containing regimens fail. Integrase resistance mutations could play a major role in phenotypic changes, such as replication capacity and drug susceptibility. The second objective of this thesis project was to compare the relative epistatic contributions of integrase, protease, reverse-transcriptase and the rest of the hiv-1 genome on viral fitness and susceptibility to raltegravir in subjects with and without raltegravir-resistance associated mutations and whose raltegravir-containing regimen has failed. Our results suggested an absence of epistatic effects between hiv-1 genes with regard to in vitro susceptibility to raltegravir. However, changes in protease, reverse-transcriptase and outside polymerase compensated for the ex vivo replication capacity of viruses containing integrase resistance mutations. Therefore, raltegravir susceptibility was essentially driven by resistance mutations within the integrase coding region, whereas other hiv-1 genes were involved in modulating viral fitness in subjects whose raltegravir-containing regimen failed. in subjects under a suppressive haart, residual viremia has been detected using ultra-sensitive methods. Whether residual viremia reflects ongoing viral replication at low levels or the production of virus from stable reservoirs remains unclear. Importantly, this question has immediate clinical implications, because if residual viremia reflects ongoing viral replication, then the intensification of the current treatment might be useful in preventing viral evolution and subsequent treatment failure. New classes of antiretroviral agents, such as integrase inhibitors, provide new tools to assess the viral reservoirs that persist in haart-suppressed subjects. Raltegravir has a unique effect on viral dna forms, leading to a measurable increase in 2-ltrs dna circles when replication is inhibited. The third objective of this project thesis was to assess whether raltegravir intensification of the haart regimen was able to impact the levels of hiv-1 dna and immune markers in subjects with undetectable viremia measured by standard assays. Raltegravir intensification in haart-suppressed subjects blocked active replication and production of infectious virus in 29 percent of subjects. Our study also revealed a causative relationship between active replication and immune activation, suggesting that under a suppressive haart, active replication is a cause rather than a consequence of aberrant immune activation. Therefore, treatment intensification disturbs the latent reservoir, with important implications for therapeutic strategies aimed at achieving viral eradication.
Datos académicos de la tesis doctoral «Effect of the hiv-1 integrase inhibitor raltegravir or drug susceptibility, replication capacity and residual viremia in hiv-infected subjects.«
- Título de la tesis: Effect of the hiv-1 integrase inhibitor raltegravir or drug susceptibility, replication capacity and residual viremia in hiv-infected subjects.
- Autor: María José Buzón Gómez
- Universidad: Autónoma de barcelona
- Fecha de lectura de la tesis: 23/09/2010
Dirección y tribunal
- Director de la tesis
- Javier Martinez Picado
- Tribunal
- Presidente del tribunal: Julián Miguel Blanco arbués
- sonsoles Sanchez palomino (vocal)
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