This repository contains the code for the manuscript entitled: 'Persistent T cell unresponsiveness associated with chronic visceral leishmaniasis in HIV-coinfected patients'. This manuscript is preprinted at https://doi.org/10.21203/rs.3.rs-2408759/v1
A large proportion of HIV-coinfected visceral leishmaniasis (VL) patients exhibit a chronic disease course with frequent recurrence of VL, despite successful viral suppression and initial parasitological cure. Due to a hard-to-reach population, knowledge on immunological determinants underlying this chronic disease course is scarce, limiting treatment and patient management options. Therefore, we studied alterations in circulatory cellular immunity of a longitudinal HIV cohort in North-West Ethiopia, including long-term cured or asymptomatic Leishmania-infected individuals, and active VL developers. Compared to non-chronic VL-HIV patients, chronic VL-HIV patients exhibited persistently high levels of TIGIT and PD-1 on both CD8+ and CD8- T cells throughout the disease course. Furthermore, these chronic VL-HIV patients showed a lower proportion of double positive IFN-γ+TIGIT- CD8+ and CD8- T cells and a higher proportion of IFN-γ-TIGIT+ CD8+ and CD8- T cells, suggestive of impaired T cell functionality. At single-cell resolution, these chronic VL-HIV patients showed marked CD4+ T cell anergy throughout their anti-leishmanial treatment, characterised by a lack of T cell activation in the transcriptome, and a lack of a lymphoproliferative response at the clonal level. These findings suggest PD-1 and TIGIT play a pivotal in VL disease chronicity in HIV co-infected patients, and that these markers may be further explored for patient risk stratification. Finally, our findings provide a strong rationale for adjunctive immunotherapy for the treatment of patients with chronic VL-HIV to break the recurrent VL disease episode cycle.