Systems biology for the identification of epigenetic biomarkers and host factors associated with hiv-1 control
- Autores: Bruna Oriol Tordera
- Directores de la Tesis: Christian Brander (dir. tes.), Marta Ruiz Riol (codir. tes.)
- Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2021
- Idioma: inglés
- Tribunal Calificador de la Tesis: José Alcamí Pertejo (presid.), Thomas Aagaard Rasmussen (secret.), Rafick Pierre Sékaly (voc.)
- Programa de doctorado: Programa de Doctorado en Inmunología Avanzada por la Universidad Autónoma de Barcelona
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
An effective HIV-1 cure is still one of the major scientific challenges, and a global solution is not yet available beyond the administration of antiretroviral drugs, which maintain undetectable viral load and pause the progression of HIV associated disease. Albeit the evident benefits of antiretroviral therapy, it is not available worldwide, it requires life-long medication and, if stopped, a rapid viral rebound is observed due to HIV-1’s capacity to establish latency and form an HIV-1 reservoir.
In the development of current HIV-1 strategies, the study of a small subset of individuals with the capacity to spontaneously control HIV-1 infection has been relevant. However, the mechanisms of this control are not fully understood. In the present thesis, we have applied different omics-based analyses to gain insight into host factors and biological mechanisms associated with natural HIV-1 control. In parallel, these analyses are also applied in the context of the BCN02 clinical trial, designed to achieve a functional HIV-1 cure, in order to identify mechanisms of post-treatment control, which might be different from the ones observed in natural control.
Chapter I describes the identification of epigenetically regulated host factors associated with spontaneous control of HIV-1. In brief, the genome-wide DNA methylation of PBMCs was studied in individuals with different levels of relative in vivo control of HIV-1 replication. Results indicated that differential DNA methylation on genes involved in the antiviral immune response and T-cell activation were associated with the capacity of natural control. Additionally, these methylation imprints were strongly associated with viral load, proviral DNA levels, markers of the T-cell response against HIV-1 and neutralizing antibody capacity. These observations indicate a crucial role of epigenetic imprints and have the potential to guide future HIV eradication and cure strategies.
The objective of Chapter II was to identify plasma biomarkers predictive of HIV-1 disease control.
Specifically, soluble forms of TL1A and DR3 were found to be associated with virus control but also with parameters of T-cell mediated immunity. These results, coupled with validation analysis and in vitro experiments, showed that DR3 stimulation enhances HIV-1 specific T cell-responses, providing a potential tool for boosting HIV- specific T-cell responses in therapeutic vaccination strategies.
Finally, an integrated systems biology analysis was conducted in the setting of the kick-and-kill intervention applied in the BCN02 clinical trial, to understand the biological mechanisms impacted by the intervention and to identify potential drivers of post-treatment control (Chapter III). Participants from the BCN02 study were treated with romidepsin to disrupt HIV-1 latency, and vaccinated with HIVconsv immunogen to elicit T-cell responses against conserved regions of HIV-1. Subsequently, individuals interrupted their antiretroviral treatment in a “monitored antiretroviral pause” (MAP) during which 4 individuals showed a delayed viral rebound and maintained viral replication below 2,000 HIV RNA copies/ml for, at least, 8 weeks. This exploratory study demonstrated how the intervention impacted the host PBMCs’ transcriptional and DNA methylation programs, especially after HIVconsv vaccination and romidepsin administration. Importantly multiple biological pathways, including the ones involved in HIV- 1 infection and T-cell immunity, were modulated at both the epigenetic and transcriptional level.
Additionally, individuals with an early or late rebound during MAP showed differential epigenetic signatures prior to treatment interruption, suggesting the use of DNA methylation-based biomarkers as a surrogate of post-treatment control.
Overall, omics-based systems biology analyses enabled the study of human plasma and PBMC samples to unveil different genes and pathways that are differentially modulated in natural and post-treatment HIV- 1 control, thus providing new potential biomarkers and therapeutic targets.
