Tesis doctoral de Gemma Moncunill Piñas
Developing new anti-hiv compounds targeting different steps of the hiv cycle is a continuous need due to the emergence of drug-resistant strains and also to the long-term toxicity of current antiretrovirals used for treatment. Hiv entry requires the binding of the viral particles to the cd4 receptor and a coreceptor through the viral envelope glycoprotein gp120, triggering structural changes in gp41 that promote the fusion of the viral and host cell membranes and viral core release into cells. Hiv strains can be classified into different tropisms depending on which coreceptor they use: ccr5 (r5), cxcr4 (x4) or both coreceptors (r5x4). Therefore, hiv entry is an essential step that offers several potential new targets for antiviral agents. From the compounds developed, coreceptor antagonists are among the most promising agents. Another class of interesting compounds are statins, which are a well-established class of drugs prescribed for treatment of hypercholesterolemia. Recent studies suggest that statins have direct anti-hiv effects both in vitro and in vivo targeting hiv entry and budding. The impact on hiv of both classes of compounds and therefore, its consequences in long-term treatment are still unknown. We wanted to characterize statins as antiretroviral agents, determine the role of coreceptor inhibitors in the evolution of hiv tropism and characterize the novel cxcr4 antagonist pol3026. Unfortunately, we could not detect a significant anti-hiv activity of statins due to a high cytotoxicity in cell culture or any effect of simvastatin in a pilot study with 12 hiv+ patients after 8-12 weeks. Using an in vitro model to study coreceptor switch of r5 strains to r5x4 or x4, we found that the probability to change coreceptor use was dependent on the clinical isolate and also on the cell-culture conditions such as availability of ccr5. We observed that selective pressure of an anti-hiv compound can modify the evolution of coreceptor use. Reverse transcriptase (rt) inhibitors and ccr5 targeting agents delayed the emergence of cxcr4-using variants compared to untreated cultures. However, cxcr4-using variants emerged faster under ccr5 drug pressure than under rt inhibitors, whereas cxcr4 antagonists could prevent its emergence. We also characterized pol3026, which proved to be a potent anti-hiv agent against naí¯ve and drug-resistant strains of x4 and r5x4 phenotype. Several assays and development of resistance allowed us to confirm that pol3026 blocked hiv replication through specific interaction with cxcr4. In conclusion, our results caution on the use of statins to treat hiv infection and on the risk that hiv may escape from ccr5 antagonists by selecting cxcr4 emerging variants. On the other hand, potent and specific cxcr4 antagonists are interesting antiviral agents that could prevent the emergence of r5x4 or x4 viruses.
Datos académicos de la tesis doctoral «Potential new therapeutic agents: effects on hiv replication and viral escape«
- Título de la tesis: Potential new therapeutic agents: effects on hiv replication and viral escape
- Autor: Gemma Moncunill Piñas
- Universidad: Autónoma de barcelona
- Fecha de lectura de la tesis: 06/02/2009
Dirección y tribunal
- Director de la tesis
- José Andrés Esté Araque
- Tribunal
- Presidente del tribunal: margarita Bofill soliguer
- eugenia Negredo puigmal (vocal)
- (vocal)
- (vocal)