Visceral leishmaniasis as an independent cause of high immune activation, T‐cell senescence, and lack of immune recovery in virologically suppressed HIV‐1‐coinfected patients

Abstract

ObjectivesDifferent immune alterations have been described in HIV-infected patients with visceral leishmaniasis (VL). We aimed to identify the immunological factors involved in the lack of immunological recovery and VL relapses in HIV-infected patients with VL, by comparison with other HIV-infected patients. MethodsWe carried out a cross-sectional study of 55 patients receiving suppressive combination antiretroviral therapy (cART) for at least 1 year: nine with previous relapsing VL, 20 with an immunodiscordant response (IDR) to cART (CD4 count < 200 cells/μL) and no previous VL, and 26 with a concordant response (CR) to cART (CD4 count > 350 cells/μL) without VL. Immunosenescence was investigated by analysing CD57 + CD28− levels, immune activation by analysing CD38 + HLA-DR + levels, inflammation by analysing interleukin (IL)-6 levels, and microbial translocation by analysing lipopolysaccharide (LPS) and soluble CD14 (sCD14) levels. ResultsIn VL patients, the median time since VL diagnosis was 42 months, and all patients had had at least one relapse despite suppressive cART for a median time of 43 months. Patients with previously diagnosed VL had a higher CD8 T-cell activation level (P < 0.001) than those with IDR. Also, levels of IL-6, LPS and especially sCD14, associated with bacterial translocation and additional monocyte activation, were significantly increased in patients with previous VL compared with patients with IDR (P = 0.048, P = 0.049 and P < 0.001, respectively). In addition, patients with previous VL had higher levels of CD8 T-cell senescence. Notably, the levels of immune activation and inflammation in patients with previous VL were not related to the time of VL diagnosis, the number of VL relapses, or hepatitis C virus (HCV) coinfection. ConclusionsOur data demonstrate that VL patients had an even worse immunological status than patients with IDR, which was probably associated with increased microbial translocation and additional monocyte/macrophage activation. These data explain the observed lack of immunological recovery and the occurrence of VL relapses in HIV-infected patients with previous VL. Specifically, visceral leishmaniasis (VL) is an infectious disease caused mainly by Leishmania donovani and Leishmania infantum (Leishmania chagasi), intracellular protozoans that infect macrophage cell lineages from lymphoid organs. It is a common coinfection in HIV-1-infected individuals in the Mediterranean basin, including Spain, with a prevalence of up to 9%. VL/HIV-1 coinfection is characterized by significantly lower cure rates, higher drug toxicity, higher relapse rates, and higher mortality rates (nearly 50%) than those for non-HIV-1-infected individuals with VL [5,6].While cART has been shown to decrease the incidence of leishmaniasis in HIV-1-infected patients, it does not seem to prevent the appearance of frequent relapses in patients previously diagnosed and largely pretreated with antiretrovirals [7][8][9], demonstrating the persistence of the parasite in different cell lines. Moreover, ...

Immune Activation and Bacterial Translocation: A Link between Impaired Immune Recovery and Frequent Visceral Leishmaniasis Relapses in HIV-Infected Patients

“…In fact, co-infected patients had high percentages of senescent CD4 + and CD8 + T lymphocytes, which reflects chronic immune activation that does not change despite the use of HAART and maintenance of anti- Leishmania treatment. This result is consistent with what has been observed in VL/HIV patients from the Mediterranean basin [30]. Our data confirm this finding through a prospective study design and in patients presenting two distinct clinical outcomes: relapse or no relapse.…”

“…The present study confirmed that co-infected patients with active VL (NR or R group) have low CD4 + T cell counts, high levels of cellular activation and microbial translocation and elevated parasitemia. In contrast to a previous study, which evaluated a single parameter [30], herein, the patient’s prior history of VL, the current immunological state of the patient at each visit and the final outcome of therapy during secondary prophylaxis were all taken into account.…”

“…Unexpectedly, this heightened cellular activation remains despite successful control of the viral and parasite loads [28] by HAART and anti- Leishmania therapy, respectively. Microbial translocation and even parasite persistence in the bone marrow or lymphoid organs have been identified as possible factors related to the maintenance of immune activation [28,30]. In this context, there is strong evidence that secondary anti- Leishmania prophylaxis helps to maintain the clinical remission of VL in HIV-infected patients [2,3,10,14].…”

Contribution of Leishmania braziliensis antigen-specific CD4+ T, CD8+ T, NK and CD3+CD56+NKT cells in the immunopathogenesis of cutaneous leishmaniasis patients: Cytotoxic, activation and exhaustion profiles

“…In this sense, assessing the frequencies of cells in exhaustion (CD279 + ), we observed an increase of NK cell frequencies in LbAgS cell cultures in all patient groups when compared with NS cultures, suggesting that NK exhaustion profile might be associated with antigenic specificity. These findings are in agreement with others that correlated the exhaustion status with antigen dependency and persistence, as well as inflammatory process that occur in CL lesions [34][35][36][37].…”

Visceral Leishmaniasis in Hospitalized HIV-Infected Patients in Pernambuco, Brazil

“…in people living with HIV produces pronounced activation of cells from the immunological system and higher production of pro-inflammatory cytokines, turning these cells into targets of the virus and these accelerate the progression to AIDS. 5,6 In some cases, it was observed activation or re-activation of latent infections by Leishmania spp., which occurs in a more immunocompromised stage caused by HIV. 7,8 Visceral leishmaniasis may be diagnosed from classic symptoms such as fever, pallor, and hepatosplenomegaly, associated with a positive serological or parasitological test.…”