High seroprevalence of Leishmania infantum is linked to immune activation in people with HIV: a two-stage cross-sectional study in Bahia, Brazil

Abstract

ABSTRACTBackgroundVisceral leishmaniasis is an opportunistic disease in HIV-1 infected individuals, although not yet recognized as a determining factor for AIDS diagnosis. The growing geographical overlap of HIV-1 and Leishmania infections is an emerging challenge worldwide, as co-infection increases morbidity and mortality for both. Here, we determined the prevalence of people living with HIV (PWH) with a previous or ongoing infection by Leishmania infantum in Bahia, Brazil and investigated the virological and immunological factors associated with co-infection.Methodology and Principal FindingsWe adopted a two-stage cross-sectional cohort (CSC) design (CSC-I, n=5,346 and CSC-II, n=317) of treatment-naïve HIV-1-infected individuals in Bahia, Brazil. In CSC-I, samples collected at the time of HIV-1 diagnosis between 1998 and 2013 were used for serological screening for leishmaniasis by an in-house immunoassay (ELISA) with SLA (Soluble Leishmania Antigen), resulting in a prevalence of previous or ongoing infection of 16.27%. Next, 317 PWH were prospectively recruited from July 2014 to December 2015 with collection of sociodemographic and clinical data. Serological validation by two different immunoassays confirmed a prevalence of 15.46% and 8.20% by anti-SLA, and anti-HSP70 serology, respectively, whereas 4.73% were double-positive (DP). Stratification of these 317 individuals in DP and double-negative (DN) revealed a significant reduction of CD4+ counts and CD4+/CD8+ ratios and a tendency of increased viral load in the DP group, as compared to DN. No statistical differences in HIV-1 subtype distribution were observed between the two groups. However, we found a significant increase of CXCL10/IP-10 (p=0.0076) and a tendency of increased CXCL9/MIG (p=0.061) in individuals with DP serology for L. infantum, demonstrating intensified immune activation in this group. These findings were corroborated at the transcriptome level in independent Leishmania- and HIV-1-infected cohorts (Swiss HIV Cohort and Piaui Northeast Brazil Cohort), indicating that CXCL10 transcripts are shared by the IFN-dominated immune activation gene signatures of both pathogens and positively correlated to viral load in untreated PWH.Conclusions/SignificanceThis study demonstrated a high prevalence of PWH with L. infantum seropositivity in Bahia, Brazil, linked to IFN-mediated immune activation and a significant decrease in CD4+ levels. Our results highlight the urgent need to increase awareness and define public health strategies for the management and prevention of HIV-1 and L. infantum co-infection.AUTHOR SUMMARYMore than 1 billion people live in areas endemic for leishmaniasis and are at risk of infection, which includes one third of the 38 million people living with HIV (PWH) worldwide. Leishmaniasis is a neglected tropical disease caused by infection with Leishmania parasites, transmitted by bites from infected sand flies. HIV/Leishmania co-infection is increasing worldwide, especially in Southern Europe and Brazil, due to both human and ecological factors (migration, climate change, deforestation). This study demonstrates that a worryingly high number (one out of 6) of PWH in Bahia (Northeast Brazil) show previous or ongoing infection with the parasite Leishmania infantum, determined by antibodies detection against this parasite in PWH. Using a rigorous study design with data collection over 18 years in >5500 PWH, we found similarly high numbers (16.3% and 15.5%) of PWH with antibodies against Leishmania infantum in two consecutive cohorts. Moreover, PWH with antibodies against Leishmania infantum in Bahia, Brazil displayed a worse immune profile, with lower CD4 immune cells numbers and immune activation mediated by interferon, which we confirmed in independent HIV- and Leishmania-infected cohorts from other geographic areas. Our results underscore the need to raise awareness and define public health strategies to prevent HIV/Leishmania co-infection, since therapeutic failure and mortality are strongly increased in co-infected PWH, even with antiretroviral therapy as standard of care.