Persistent T-cell dysfunction in synergistic VL-HIV co-infection

Co-infection of Human Immunodefiency Virus (HIV) and visceral leishmaniasis (VL) is characterized by an unsatisfying clinical management of patients, with frequent VL relapse and high case-fatality rates. In clear contrast with other HIV co-infections, VL-HIV patients present a highly suppressed cellular immunity that progresses, despite viral load suppression, towards an unparalleled chronic condition of immunological ‘tolerance’ to the parasite. An in depth understanding of how HIV modulates protective patterns of VL and whether this defines the lack of immune recovery in coinfected patients is lacking. We hypothesize that due to HIV co-infection, specific protective T-cell mechanisms against VL are progressively impaired, leading to a persistently depressed T-cell immunity inciting the unique clinical manifestation of VL-HIV co-infection. By means of an
unprecedented cohort study of HIV individuals in a VL-endemic area in Ethiopia, I have the rare opportunity to follow single patients across early to late stages of the co-infection and comprehensively characterize the evolution of the persistent T-cell dysfunction and its real-time association with clinical events. To explore beyond simplified paradigms, I will apply a systems biology approach including a novel tracking of the transcriptional roadmap of the protective T-cell lineage at single cell level to characterize the unknown pathway towards T-cell dysfunction and dissect the heterogeneity within this lineage.