Identification of immune mechanisms that are associated with visceral leishmaniasis relapse in patients with visceral leishmaniasis and HIV co-infection

Abstract

Visceral leishmaniasis (VL) has emerged as a clinically important opportunistic infection in HIV-positive patients, as VL/HIV co-infected patients suffer from increased treatment failure, drug toxicity, mortality and VL relapse. Here, I followed cohorts of patients with VL only and co-infected with HIV in Ethiopia and collected detailed clinical and immunological data during 12 months of follow-up, to identify clinical and immunological markers that are associated with VL relapse. By the end of the study, 78.1% of VL/HIV patients, but none of the VL-only patients, had experienced VL relapse. Despite clinical and/or parasitological defined cure at the end of antileishmanial treatment, over time VL/HIV patients maintained high parasite loads, splenomegaly, low BMI, pancytopenia, high levels of programmed cell death protein 1 (PD1) on CD4+ and CD8+ T cells, impaired IFN-γ production capacity in a whole blood assay (WBA) and persistently high level of inflammatory cytokines. In contrast, these parameters were restored over time in patients with VL infection only. Furthermore, during follow-up these parameters were also associated with VL relapse in VL/HIV co-infection. Overall, my results suggest that in VL/HIV patients, VL relapses independent of the HIV viral load and the high rate of VL relapse in VL/HIV patients is at least in part due to their impaired capacity to restore CD4+ T cell counts and antigen-specific IFN-γ production in the whole blood assay; as well as high levels of the inhibitory molecule PD1 on T cells and high levels of pro- and anti-inflammatory cytokines in the plasma. Furthermore, the impaired IFN-γ production and the persistently high levels of PD1 on T cells in VL/HIV patients suggests that these patients might also benefit from immunotherapy with IFN-γ and anti-PD1.