Towards an HIV cure Characterization of the viral reservoir and host-targeted approaches

Achieving an HIV-1 cure remains challenging due to the persistence of a stable viral reservoir that is not eliminated by antiretroviral therapy. This thesis focuses on the characterization of the HIV-1 reservoir and explores host-targeted strategies as potential approaches to disrupt viral infection and transmission. By integrating reservoir profiling with mechanistic studies of host-virus interactions, it provides a broader understanding of the forces sustaining HIV-1 persistence. The first part of this work examines key cellular programs that underlie HIV-1 latency and reservoir maintenance across different immune cell types. The findings indicate that viral persistence is not driven by a single dominant mechanism, but instead arises from a combination of host cell states and cellular processes that together create a permissive environment for proviral silencing and long-term survival. The second part translates these insights into potential therapeutic strategies by targeting host factors involved in viral dissemination and replication. This approach demonstrates that interfering with host-virus interactions can effectively limit HIV-1 spread and may complement existing antiviral therapies. Overall, this thesis underscores that HIV-1 persistence is driven by complex host-virus interactions and is unlikely to be resolved by virus-targeted approaches alone. Instead, it supports the development of multipronged strategies that combine a deeper understanding of reservoir biology with host-directed interventions to move closer toward durable HIV-1 remission.