PhD defence E. (Enrico) Ne

Since the discovery of HIV-1 as the causative agent of acquired immunodeficiency syndrome (AIDS), in 1983/1984, significant advances have been made in understanding the molecular pathogenesis of the infection. While the virus constantly mutating nature has made it impossible to develop an effective vaccine, the development of highly effective antiviral drugs and the advent of combination antiretroviral therapy (cART) has allowed the reduction of AIDS-associated mortality and prevented transmission to uninfected individuals. Despite these successes, the quest for an HIV-1 cure remains a global priority as cART is not curative, has side effects, and must be taken lifelong. Additionally, the global roll-out of cART, particularly in resource-limited countries, remains an ongoing challenge. HIV-1 persists because, following infection, the provirus can establish latent infection in resting CD4+ T cells and other long-lived immune cell populations. Due to this reservoir of long-lived latently HIV-1 infected cells, interruption of cART leads to a rapid rebound of unrestricted viral replication, necessitating life-long treatment. Therapeutic strategies for HIV-1 cure aim to eliminate, inactivate, or reduce the pool of latently infected cells such that the patient’s immune system can control viral replication upon cessation of cART. A popular strategy is to induce viral production in latently infected cells, using drug interventions referred to as latency reversal agents (LRAs), to render the infected cell recognizable to the immune system or susceptible to viral cytopathic effects for elimination. In this thesis, we developed three different and complementary discovery tools that have led to the identification of novel molecular targets, critical for HIV-1 latency and novel small molecule latency reversal agents (LRAs) that can be exploited for therapeutic interventions aiming at reversing latency. This work further expands the known repertoire of factors and cellular pathways that determine viral latency (described in the general introduction: Chapter 1) and contributes to a better understanding of the mechanisms and routes that can be targeted by latency reversal strategies.

Due to corona, the PhD defences do not take place publicly in the usual way in the Senate Hall or in the Professor Andries Querido Room. The candidates will defend their dissertation either in a small group or online.