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

Silva-Freitas, Maria Luciana; Cota, Gláucia; Machado-de-Assis, Talia S.; Giacoia-Gripp, Carmem Beatriz Wagner; Rabello, Ana; Da‐Cruz, Alda Maria; Santos-Oliveira, Joanna Reis

doi:10.1371/journal.pone.0167512

Cited by 18 publications

(30 citation statements)

References 42 publications

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“…We showed that relapsing-VL/HIV patients maintained low CD4 + T lymphocyte counts, higher percentages of activated CD4 + and CD8 + T cells, sCD14 and anti-Leishmania IgG3, even 12 months after anti-leishmanial treatment, whereas this immune profile was reverted in non-relapsing-VL/HIV patients after anti-Leishmania treatment (13). This indicates intense activation leading to an exhaustion of the immune response to the parasite, which may contribute to the frequent VL relapses or even faster disease progression (2,14).…”

Section: Introductionmentioning

confidence: 80%

“…Accordingly, it is conceivable that the compromising degree of one of these compartments may be related to a deficient immune response. These features may contribute to the lack of parasite control which in turn could explain the frequent relapses in VL/HIV (13,14). Thus, the aim of this study was to evaluate if the gain of T cells observed in NR-VL/HIV patients after anti-Leishmania treatment (13) was related to changes in the mobilization profile of the peripheral TCRVβ repertoire, and whether the thymus is involved in the replenishment of newly T cells, especially in non-relapsing VL/HIV co-infected patients.…”

Section: Introductionmentioning

confidence: 99%

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Impaired Thymic Output Can Be Related to the Low Immune Reconstitution and T Cell Repertoire Disturbances in Relapsing Visceral Leishmaniasis Associated HIV/AIDS Patients

et al. 2020

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Silva-Freitas et al. Thymic Impairment in VL/HIV Patients Results: VL/HIV cases presented an altered mobilization profile (expansions or retractions) of the TCRVβ families when compared to HS independent of the follow-up phase (p < 0.05). TCRVβ repertoire on CD4 + T-cells was more homogeneous in the NR-VL/HIV cases, but heterogeneous on CD8 + T-cells, since different Vβ-families were mobilized. NR-VL/HIV had the inflammatory pattern reduced after 6 mpt. Importantly, VL/HIV patients showed number of TREC copies lower than controls during all follow-up. An increase of recent thymic emigrants was observed in NR-VL/HIV individuals at 10 mpt compared to R-patients (p < 0.01), who maintained lower TREC contents than the HIV controls. Conclusions: VL/HIV patients that maintain the thymic function, thus generating new T-cells, seem able to replenish the T lymphocyte compartment with effector cells, then enabling parasite control.

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Section: Introductionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Impaired Thymic Output Can Be Related to the Low Immune Reconstitution and T Cell Repertoire Disturbances in Relapsing Visceral Leishmaniasis Associated HIV/AIDS Patients

et al. 2020

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“…Likewise, VL was reported as an independent cause of increased non-specific immune activation, T cell senescence and the lack of immune recovery in virologically suppressed coinfected HIV patients ( 56 , 57 ). In line with T cell exhaustion, chronic immune activation was recently associated with recurrent relapse of VL in HIV patients ( 58 ). Recent research in VL–HIV patients also suggested that weak antigen-specific functional responses or proliferation of T cells after in vitro stimulation was an important predictor of relapse ( 59 ).…”

Section: Immunopathogenesis Of Vl–hiv Coinfectionmentioning

confidence: 98%

Immunomodulatory Therapy of Visceral Leishmaniasis in Human Immunodeficiency Virus-Coinfected Patients

et al. 2018

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Patients with visceral leishmaniasis (VL)–human immunodeficiency virus (HIV) coinfection experience increased drug toxicity and treatment failure rates compared to VL patients, with more frequent VL relapse and death. In the era of VL elimination strategies, HIV coinfection is progressively becoming a key challenge, because HIV-coinfected patients respond poorly to conventional VL treatment and play an important role in parasite transmission. With limited chemotherapeutic options and a paucity of novel anti-parasitic drugs, new interventions that target host immunity may offer an effective alternative. In this review, we first summarize current views on how VL immunopathology is significantly affected by HIV coinfection. We then review current clinical and promising preclinical immunomodulatory interventions in the field of VL and discuss how these may operate in the context of a concurrent HIV infection. Caveats are formulated as these interventions may unpredictably impact the delicate balance between boosting of beneficial VL-specific responses and deleterious immune activation/hyperinflammation, activation of latent provirus or increased HIV-susceptibility of target cells. Evidence is lacking to prioritize a target molecule and a more detailed account of the immunological status induced by the coinfection as well as surrogate markers of cure and protection are still required. We do, however, argue that virologically suppressed VL patients with a recovered immune system, in whom effective antiretroviral therapy alone is not able to restore protective immunity, can be considered a relevant target group for an immunomodulatory intervention. Finally, we provide perspectives on the translation of novel theories on synergistic immune cell cross-talk into an effective treatment strategy for VL–HIV-coinfected patients.

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“… 11 , 12 Also, chronic immunostimulation induced by Leishmania enhances the multiplication of HIV and further progression of HIV infection to AIDS, depressing immunity by exhaustion of immune resources. 11 , 13 , 14 Therefore, Leishmania –HIV coinfection has negative effects, generating poor outcomes and higher risk of relapse in coinfected patients. Even after successful treatment and HAART use, coinfected individuals present increased levels of CD38 + CD8 + T lymphocytes (pointing to increased cellular activation) and proinflammatory cytokines (MIF, MIP1β, TNF, IL6, IL8, and IL17).…”

Section: Immunoresponse In Vl–hiv-infected Patientsmentioning

confidence: 99%

“…In this way, they have chronic immunoactivation induced by persistence of parasites and/or by microbial translocation though the intestinal barrier, demonstrated by the presence of elevated levels of lipopolysaccharide, soluble CD14, and IFBP in serum levels, the immunopathogenic basis of which could be related to mucosal invasion by amastigotes and systemic lymphocyte depletion. 13 , 15 …”

Section: Immunoresponse In Vl–hiv-infected Patientsmentioning

confidence: 99%

Visceral leishmaniasis and HIV coinfection: current perspectives

Lindoso¹,

Moreira²,

Cunha³

et al. 2018

HIV

112

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Visceral leishmaniasis (VL) is caused by Leishmania donovani and Leishmania infantum. The burden of VL is concentrated in tropical and subtropical areas; however, HIV infection has spread VL over a hyperendemic area. Several outcomes are observed as a result of VL–HIV coinfection. Impacts are observed in immunopathogenesis, clinical manifestation, diagnosis, and therapeutic response. Concerning clinical manifestation, typical and unusual manifestation has been observed during active VL in HIV-infected patient, as well as alteration in immunoresponse, inducing greater immunosuppression by low CD4 T-lymphocyte count or even by induction of immunoactivation, with cell senescence. Serological diagnosis of VL in the HIV-infected is poor, due to low humoral response, characterized by antibody production, so parasitological methods are more recommended. Another important and even more challenging point is the definition of the best therapeutic regimen for VL in HIV-coinfected patients, because in this population there is greater failure and consequently higher mortality. The challenge of better understanding immunopathogenesis in order to obtain more effective therapies is one of the crucial points to be developed. The combination of drugs and the use of secondary prophylaxis associated with highly active antiretroviral therapy may be the best tool for treatment of HIV coinfection. Some derivatives from natural sources have action against Leishmania; however, studies have been limited to in vitro evaluation, without clinical trials.

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

Cited by 18 publications

References 42 publications

Impaired Thymic Output Can Be Related to the Low Immune Reconstitution and T Cell Repertoire Disturbances in Relapsing Visceral Leishmaniasis Associated HIV/AIDS Patients

Impaired Thymic Output Can Be Related to the Low Immune Reconstitution and T Cell Repertoire Disturbances in Relapsing Visceral Leishmaniasis Associated HIV/AIDS Patients

Immunomodulatory Therapy of Visceral Leishmaniasis in Human Immunodeficiency Virus-Coinfected Patients

Visceral leishmaniasis and HIV coinfection: current perspectives

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