Identification and characterization of novel latency-reversing agents to clear hiv-1 viral reservoir
- Autores: Edurne García Vidal
- Directores de la Tesis: Ester Ballana (dir. tes.)
- Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2019
- Idioma: español
- Tribunal Calificador de la Tesis: Andreas Meyerhans (presid.), María José Buzón Gómez (secret.), Albert Jordan Valles (voc.)
- Programa de doctorado: Programa de Doctorado en Inmunología Avanzada por la Universidad Autónoma de Barcelona
- Materias:
- Enlaces
- Tesis en acceso abierto en: TESEO
- Resumen
Current antiretroviral therapy has changed the perspective of HIV-1 infection from a lethal illness to a chronic disease. However, the HIV-1 latent reservoir is a major hurdle to achieve a cure for HIV-1. The “shock and kill” strategy is based on inducing viral transcription of latent HIV-1 provirus followed by the selective killing of reactivated cells. Although several latency-reversing agents (LRAs) have been identified and tested, none of them has been able to efficiently eradicate the HIV-1 latent reservoir. Based on the need of novel agents and strategies to efficiently clear the latent reservoir, we evaluated compounds developed as modulators of the innate immune response or designed to modulate the cell cycle progression as novel agents able to purge the viral reservoir.
The study of innate immune modulators as agents able to clear the HIV-1 reservoir might represent an alternative due to its intrinsic functions, i. e., protection and clearance of infections. The innate immune regulator acitretin, an FDA-approved compound for psoriasis, has been proposed to induce HIV-1 reactivation and selective killing of the infected cells. However, the effect of acitretin on HIV-1 reactivation was negligible in the vast majority of models tested, albeit activation of RIG-I pathway was detected and a mild induction of viral reactivation was observed in a non-clonal T cell model. Moreover, acitretin treatment did not induce the selective killing of the infected cells.
Anti-cancer compounds have also been proposed as candidate therapies targeting the latent reservoir, mainly due to the ability of certain agents to modify gene transcription or to promote cell apoptosis. The assessment of the HIV-1 reactivation potential of an anti-cancer compound library reported several molecular targets whose inhibition promoted HIV-1 latency reversal, including the histone deacetylases (HDAC), Janus kinases (JAK), IκB kinases (IKKs) and heat shock proteins (HSPs). Among the new identified LRAs, Aurora kinases inhibitors (AURKi) represented the largest family of compounds not previously described as LRA that significantly and consistently showed HIV-1 reactivation capacity. AURKi were able to enhance the HDACi-mediated reactivation, suggesting that AURKi are able to target a distinct set of integrated provirus than that reactivated by the well-described HDAC inhibitors. Interestingly, AURKi restricted acute HIV-1 infection, suggesting a dual role for these compounds on HIV-1 infection.
Midostaurin, a multi-kinase inhibitor approved for leukemia treatment, was also identified as an LRA. Midostaurin induced HIV-1 latency reactivation, either alone or in combination with other LRAs, consistent with previous reports that associated this activity with the activation of the innate immune NF-κB pathway. Moreover, we also observed a non-yet-reported and SAMHD1-dependent inhibitory effect of HIV-1 replication in primary cells.
The enhanced capacity to promote HIV-1 reactivation of AURKi and midostaurin in combination with other LRAs supports the idea that different agents are needed to reactivate all latent provirus, presenting different specificities towards HIV-1 provirus reactivation depending on its integration site in the host genome. Furthermore, these observations also raise concerns on the models used to study HIV-1 latency, as clonal models might not be suitable due to the lack of heterogeneity in proviral insertion site, characteristic of non-clonal models. Altogether, our results suggest that modulation of innate immunity and cell cycle may be taken into account for the design of future LRAs for the “shock and kill” strategy; however, further research is still necessary before it can lead to an HIV-1 cure.
