Persistent T cell unresponsiveness associated with chronic visceral leishmaniasis in HIV-coinfected patients

Abstract 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. Thus, we studied alterations in cellular immunity with flow cytometry and single-cell RNA and T cell receptor sequencing on circulatory immune cells of a longitudinal HIV cohort in North-West Ethiopia, including asymptomatically Leishmania -infected and active VL-HIV patients. We observed that VL chronicity in VL-HIV patients was associated with persistent CD8 + T cell exhaustion and marked CD4 + T cell anergy, characterised by a high expression of PD-1 and TIGIT, and a lack of lymphoproliferative response upon stimulation. These findings provide a strong rationale for adjunctive immunotherapy for the treatment of chronic VL-HIV patients and highlight the importance of VL relapse markers.