Abortive HIV-1 RNA in the induction of immunity Shaping immune responses via viral sensors

Our immune system is exposed to microbial pathogens on a daily basis. To protect ourselves from these ongoing threats, immune cells highly rely on immune surveillance mechanisms to alarm the cell when needed to eliminate these threats. The human immunodeficiency virus type 1 (HIV-1) is known for its ability to evade host immune surveillance in various ways. Dendritic cells (DCs), a specialized type of immune cells involved in the induction of both innate and adaptive immunity, have the capacity to detect multiple HIV-1 pathogen-associated molecular patterns (PAMPs) via host pattern recognition receptors (PRRs). In this thesis, we describe how abortive HIV-1 RNA, an HIV-1 PAMP, induces immunity via different PRRs. We focused on the viral PRRs DDX3 and PKR and on the molecular mechanisms responsible for the induction of immunity. We demonstrated that DDX3-dependent sensing of abortive HIV-1 RNA induced antiviral type I IFN responses via antiviral protein MAVS, while PKR-dependent sensing induced pro-inflammatory responses. Furthermore, we challenged the viral sensing mechanisms to investigate which regions of abortive HIV-1 RNA are important for viral sensing and subsequent antiviral and pro-inflammatory responses. The research described in this thesis identifies various targets, such as viral sensors DDX3 and PKR but also their downstream signaling molecules, that could help boost or interfere with antiviral or pro-inflammatory responses, respectively. Collectively, we show that abortive HIV-1 RNA is a versatile HIV-1 PAMP with the capacity to elicit many different types of immune responses, establishing abortive HIV-1 RNA as an interesting adjuvant for vaccine design strategies.