T-cell activation, senescence, and exhaustion in asymptomatic HIV-Leishmania infantum co-infection

BackgroundLeishmania infantum is an opportunistic parasitic infection. An immunocompromised state increases the risk of converting asymptomatic infection to symptomatic visceral leishmaniasis (VL), which has a [~]5% fatality rate even with treatment. HIV coinfection increases the risk of death from VL. MethodsA cross-sectional study was performed between 2014 and 2016 to determine the prevalence of L. infantum infection in HIV positive subjects residing in the state of Rio Grande do Norte, Brazil (n=1,372) and of these a subgroup of subjects were followed longitudinally. Subsequent incident cases of VL were ascertained from a public health database through 2018. A subgroup (n=69) of the cross-sectional study subjects was chosen to assess immune status (T cell activation, senescence, exhaustion) and outcome. The data were compared between asymptomatic HIV+/L. infantum+ (HIV/Leish), symptomatic visceral leishmaniasis (VL), recovered VL, DTH+ (Delayed-Type Hypersensitivity response - Leishmanin skin test), AIDS/VL, HIV+ only (HIV+), and Non-HIV/Non L. infantum infection (control subjects). ResultsThe cross-sectional study showed 24.2% of HIV+ subjects had positive anti-IgG Leishmania antibodies. After 3 years, 2.4% (8 of 333) of these HIV/Leish coinfected subjects developed AIDS/VL, whereas 1.05% (11 of 1,039) of HIV subjects with negative leishmania serology developed AIDS/VL. Poor adherence to antiretroviral therapy (p=0.0008) or prior opportunistic infections (p=0.0007) was associated with development of AIDS/VL. CD4+ (p=0.29) and CD8+ (p=0.38) T cells counts or viral load (p=0.34) were similar between asymptomatic HIV/Leish and HIV subjects. However, activated CD8+CD38+HLA-DR+ T cells were higher in asymptomatic HIV/Leish than HIV group. Likewise, senescent (CD57+) or exhausted (PD1+) CD8+ T cells were higher in asymptomatic HIV/Leish than in AIDS/VL or HIV groups. ConclusionAlthough asymptomatic HIV/Leish subjects had normal and similar CD4+ and CD8+ T cells counts, their CD8+T cells had increased activation, senescence, and exhaustion, which could contribute to risk of developing VL. Author SummaryThe frequency of asymptomatic HIV/Leishmania infantum (HIV/Leish) infection and the immunological status of subjects with HIV+ residing in the state of Rio Grande do Norte, Brazil, between 2014 and 2016 were studied. A high frequency of asymptomatic HIV/Leishmania infantum infection (HIV subjects with positive anti-IgG Leishmania antibodies) was found. Asymptomatic HIV/Leish subjects had CD8 T cells with higher markers of activation, senescence and exhaustion than the other groups (HIV-alone, symptomatic VL, Recovered VL, DTH+, AIDS/VL and Controls subjects). Poor adherence to antiretroviral therapy or history of previous opportunistic infection was associated with AIDS/VL. Asymptomatic HIV/Leish had high relative risk of developing AIDS/VL. Thus, subjects with HIV residing in endemic areas for VL should be assessed for their L. infantum infection status and advised to closely adhere to ART.