Reduction and elimination of HIV reservoirs
The development of potent antiretroviral treatment (ART) strategies has significantly changed the face of the HIV/AIDS pandemic from a lethal disease to a chronic livable condition for infected individuals with access to care. However, in spite of ground-breaking advances in anti-HIV treatment, cure or eradication attempts have so far failed. Indeed, once HIV establishes infection, the virus persists as an integrated complementary DNA within the host cell genome in a small population of cells. While these persistently infected cells are rare in individuals on ART, they remain fairly stable over time and interruption of ART leads to a rebound of viremia. Daunting data from animal models suggest that an HIV reservoir is already established during the first days of acute infection that can only be minimised through very early ART initiation.
While latently infected cells harbor HIV DNA, they express little or no viral RNA and viral proteins, typically rendering them beyond the reach of immune surveillance. Strategies aimed at reactivating latent virus and thereby facilitating the clearance of this reservoir by the immune system have so far failed.
The latent viral reservoir in memory and naïve resting CD4 T cells constitutes a small pool of cells which can harbor HIV-1 proviruses, from which a viral rebound can occur upon discontinuation of therapy. However, how latency is established, which types of cells as a whole comprise the latent reservoir and how latency can be overcome is poorly understood. The development of a successful cure strategy will require unravelling the mechanisms that maintain HIV-1 proviruses in a latent state and pathways that drive the proliferation of provirus-carrying CD4 T cells, which also slows reservoir decay. Identifying, selectively targeting and ultimately eliminating the latent reservoir in HIV-infected individuals are critical steps towards cure. Likely, a combination of effective immunological, pharmacological and/or genetic approaches will have to be developed to purge the persistent reservoir of HIV. Approaches to genetically manipulate resting CD4 T cells in the context of mechanistic studies and thus the functional validation of identified biomarkers have been hampered by the lack of suitable experimental approaches. Low efficiency of RNA interference or high toxicity have posed major barriers for addressing the role of specific cellular factors in regulating the susceptibility to the virus, innate recognition of infection, the establishment of latency and HIV reactivation. This warrants the development of fundamentally new experimental approaches.
Within the project “Reduction and elimination of HIV reservoirs” we have defined three major goals in a bench-to-bedside pipeline towards HIV cure:
- We aim to develop and apply innovative methodology and molecular insight gained by our investigators to understand cellular and viral mechanisms of HIV-1 persistence, latency and reactivation and how these reservoirs can be identified and targeted by surface-exposed biomarkers or through druggable metabolic characteristics in vitro, in ex vivo models and in animal models of lentiviral infection.
- Building on these efforts, we seek to translate these findings to clinical observational studies to further validate specific signatures of the HIV reservoir and to design and develop promising interventional approaches. At least one of the findings shall be advanced to the clinics to selectively target and ultimately eliminate the latent reservoir.
- Finally, to further characterize the nature of the latent reservoir in HIV patients, we will comprehensively determine and quantify sites of HIV persistence and replication in tissues and cells from deceased, on long-term antiretroviral treatment (ART) HIV-infected individuals in a “whole body reservoir” approach as well as in selected compartments in patient cohorts with acute HIV infection.
