Resumen de Challenges and prospects for an immune-driven functional cure of hiv infection
Human Immunodeficiency Virus (HIV) infection causing the Acquired Immune Deficiency Syndrome (AIDS) is one of the major pandemics of our time. In 2018, 1.7 million of new infections occurred and over 37.9 million people were estimated to be living with HIV-1 infection. Although combined antiretroviral therapy treatment (ART) can suppress viral replication and has led to dramatically reduced AIDS-related mortality, it is not able to cure the infection. Moreover, ART present some major inconvenients, including the need for lifelong adherence, daily dosing and several long-term side effects. In addition, the cost of ART is high, which makes it not accessible to many individuals living with HIV, especially among people in low- and middle-income countries. For these reasons, the development of an effective preventive vaccine and a cure strategy are of greatest importance to achieve the end of the HIV pandemic.
However, the development of a preventive vaccine and an effective cure for HIV has proven to be one of the major scientific challenges of our times. In order to develop a cure, we need to better understand the mechanisms that underpin immune-mediated control of HIV so that these insights can be incorporated into new immune interventions. Moreover, understanding the processes by which the virus is able to persist upon ART and how we can reverse HIV latency is critical in order to develop new interventions that aim to halt HIV persistence. We believe that a successful HIV cure intervention will require a combined approach able to both, reactivate the virus as well as to induce an immune response able to clear latently infected cells.
In this thesis, we aim to provide a better understanding of the mechanisms mediating HIV immune control as well as to define potential immune correlates of control in intervention clinical trials. The first two chapters of the thesis are focused on identifying potential virological and immune correlates of control that could be used as predictive markers when evaluating efficacy outcomes in intervention clinical trials. The second part of the thesis is focused on the BCN02 clinical trial, the first kick&kick clinical trial that has shown some level of post-intervention viral control. The BCN02 clinical trial tested, in early-treated individuals, the effect of a therapeutic vaccine designed to induce HIV-specific responses towards the most conserved domains of HIV combined with the histone deacetylase inhibitor romidepsin, given as a latency reversing agent (LRA). Altogether, the results from the second part of the thesis support the potential of kick&kill strategies in achieving a durable immune-mediated HIV-1 control. Additionally, the comprehensive characterization of the in vivo effects of romidepsin could be incorporated into optimized combination regimens of LRA and vaccines in the future.
In summary, this work provides an overview of one of the many strategies that are being pursued to attain an HIV cure, starting from finding better correlates of control and finally testing an HIV cure strategy in human clinical trials. We believe that the key for an effective HIV cure relies on finding a way to reactive the virus from latently infected cells and finding an optimized vaccine candidate able to effectively re-educate the immune response to clear infected cells. Achieving the best design and combination of these two components has proved to be very challenging. We hope that all the scientific knowledge in the HIV field obtained during the last 30 years, along with all the currently ongoing and future clinicals trials testing new therapeutic strategies such as the ones presented in this thesis, will ultimately contribute to the development of an effective HIV cure strategy.
