Rna interference as antiretroviral strategy: search of new cellular targets and mechanisms of therapeutic application
- Autores: Eduardo Pauls García
- Directores de la Tesis: José Andrés Esté Araque (dir. tes.)
- Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2008
- Idioma: español
- Tribunal Calificador de la Tesis: Dolores Jaraquemada Pérez de Guzmán (presid.), Miguel Ángel Martínez de la Sierra (secret.), Adolfo Rio Fernandez (voc.)
- Materias:
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- Resumen
RNA interference is considered a potential source of new therapeutic approaches to treat HIV infection. Then, the study of the off-target effects mediated by RNA interference molecules and the virus capacity to escape from interference restriction should be a relevant focus of study.
We have provided evidence of non-specific, unwanted effects of a series of siRNAs that had been tested as candidate anti-HIV agents and shown to specifically block HIV coreceptor CCR5 expression. Independently of their potency as inhibitors of HIV replication and apparent specificity for the HIV coreceptor, siRNAs targeting CCR5 were able to induce the production of IL-6, IL-8 or both.
In the other hand, shRNA can be a valid alternative for a durable HIV replication inhibition, but one should be aware of the appearance of resistant variants that can overcome the restriction. We found that, although the targeted region encodes for two essential viral proteins, the virus could escape and maintained its replication capacity and drug sensitivities similar to that of the wild-type strain.
Moreover, RNA interference may be an important tool for the study of cellular factors involved in HIV replication. Protocols for the identification and characterization of cellular cofactors should help to understand virus-host interactions. This thesis shows two examples of how RNAi technology may be useful in the study of cellular factors that cooperate in different ways with HIV: p53 and integrin alphaV.
Our results showed two different roles for p53 in HIV-1 infection: a cooperative effect with the transcriptional machinery to promote LTR transcription, and a pro-apoptotic function in the death of envelope-induced syncytia Finally, defining the cellular factors and mechanisms involved in the regulation of HIV infection in macrophages could be important for the long term goal of eradicating viral reservoirs in infected patients. AlphaV integrin interference confirmed that cell adhesion through alphaV-containing integrins is required for efficient HIV-1 infection in macrophages.
