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Add-on Pyridostigmine Enhances CD4+ T-Cell Recovery in HIV-1-Infected Immunological Non-Responders: A Proof-of-Concept Study.

ABSTRACT: In human immunodeficiency virus (HIV)-infection, persistent T-cell activation leads to rapid turnover and increased cell death, leading to immune exhaustion and increased susceptibility to opportunistic infections. Stimulation of the vagus nerve increases acetylcholine (ACh) release and modulates inflammation in chronic inflammatory conditions, a neural mechanism known as the cholinergic anti-inflammatory pathway (CAP). Pyridostigmine (PDG), an ACh-esterase inhibitor, increases the half-life of endogenous ACh, therefore mimicking the CAP. We have previously observed that PDG reduces ex vivo activation and proliferation of T-cells obtained from people living with HIV.We conducted a 16-week proof-of-concept open trial using PDG as add-on therapy in seven HIV-infected patients with discordant immune response receiving combined antiretroviral therapy, to determine whether PDG would promote an increase in total CD4+ T-cells. The trial was approved by the Institutional Research and Ethics Board and registered in ClinicalTrials.gov (NCT00518154).Seven patients were enrolled after signing informed consent forms. We observed that addition of PDG induced a significant increase in total CD4+ T-cells (baseline?=?153.1?±?43.1 vs. week-12?=?211.9?±?61.1?cells/µL; p?=?0.02). Post hoc analysis showed that in response to PDG, four patients (57%) significantly increased CD4+ T-cell counts (responders?=?257.8?±?26.6 vs. non-responders?=?150.6?±?18.0?cells/µL; p?=?0.002), and the effect persisted for at least 1?year after discontinuation of PDG.Our data indicate that in patients with HIV, add-on PDG results in a significant and persistent increase in circulating CD4+ T-cells.

SUBMITTER: Valdes-Ferrer SI

PROVIDER: S-EPMC5651246 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Add-on Pyridostigmine Enhances CD4<sup>+</sup> T-Cell Recovery in HIV-1-Infected Immunological Non-Responders: A Proof-of-Concept Study.

Valdés-Ferrer Sergio I SI Crispín José C JC Belaunzarán-Zamudio Pablo F PF Rodríguez-Osorio Carlos A CA Cacho-Díaz Bernardo B Alcocer-Varela Jorge J Cantú-Brito Carlos C Sierra-Madero Juan J

Frontiers in immunology 20171018

<h4>Background</h4>In human immunodeficiency virus (HIV)-infection, persistent T-cell activation leads to rapid turnover and increased cell death, leading to immune exhaustion and increased susceptibility to opportunistic infections. Stimulation of the vagus nerve increases acetylcholine (ACh) release and modulates inflammation in chronic inflammatory conditions, a neural mechanism known as the <i>cholinergic anti-inflammatory pathway</i> (CAP). Pyridostigmine (PDG), an ACh-esterase inhibitor, i ...[more]

PMID: 29093707

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Project description:BackgroundCD4+ T cell counts in certain human immunodeficiency virus (HIV)-infected patients called immunological non-responders (INRs) could not return to a normal level even with sustained antiretroviral therapy (ART) because of persistent immune activation, which is associated with pro-inflammatory cytokines production and an altered intestinal microbiome profile. Changes in gut bacterial composition have been linked to low CD4+ T cell counts in HIV-infected individuals. However, the association between CD4+ T cell counts and gut microbiota community composition and cytokines levels in INRs (CD4+ T cell counts < 500 cells/μL) from Yunnan Province, China, has not been previously investigated.MethodsTo address this issue, we carried out a cross-sectional study of 34 HIV-infected INRs. The patients were divided into CD4 count > 200 cells/μL group and CD4 count < 200 cells/μL group. The gut microbiota composition of each subject was analyzed by 16S rRNA gene sequencing. We also compared CD8+ T cell counts, pro-inflammatory cytokines levels, and nutritional status between the two groups.ResultsCompared to INRs with CD4 count > 200 cells/μL, those with CD4 count < 200 cells/μL had a lower CD4/CD8 ratio, lower nutritional status and higher serum levels of tumor necrosis factor (TNF)-α, interferon-γ-inducible protein (IP)-10 and interleukin (IL)-1α. Ruminococcaceae was less abundant in the CD4 count < 200 cells/μL group than in the CD4 count > 200 cells/μL group, and difference in alpha diversity was observed between the two groups. Moreover, CD4+ T cell counts were negatively associated with TNF-α and IL-1α levels and positively associated with the relative abundance of Ruminococcaceae.ConclusionsOur study demonstrated that lower CD4+ T cell counts in INRs are associated with a reduced abundance of Ruminococcaceae in the gut and elevated serum pro-inflammatory cytokines levels. Thus, interventions targeting gut microbiota to increase CD4+ T cell counts are a potential strategy for promoting immune reconstitution in HIV-infected INRs.

Project description:BACKGROUND:Introduction of antiretroviral therapy (ART) in sub-Saharan Africa was a hot debate due to many concerns about adherence, logistics and resistance. Currently, it has been significantly scaled up. However as the WHO clinico-immunological approaches for initiation and monitoring of ART in the region lacks viral load determination and drug resistance monitoring, HIV infected adults and children may be at risk for "unrecognized" virologic failure and the subsequent development of antiretroviral drug resistance. This study evaluates the virological efficacy and immunological recovery of HIV/AIDS patients under ART. METHODS:Consecutive HIV-1 infected adults (N = 100) and children (N = 100) who have been receiving ART for up to 6 years at Gondar University Hospital, Ethiopia were enrolled following the WHO protocol for assessment of acquired drug resistance. Magnitude of viral suppression, genotypic drug resistance mutations and patterns of CD4+ T cell recovery were determined using standard virological and immunological methods. RESULTS:Virological suppression (HIV RNA < 40 copies/ml) was observed in 82 and 87% of adults and children on a median time of 24 months on ART, respectively. Mutation K103N conferring resistance to non nucleoside reverse transcriptase inhibitors and thymidine analogue mutations (M41L, L210W) were found only in one adult and child patient, respectively. Median CD4+ T cell count has increased from baseline 124 to 266 (IQR: 203-306) and 345 (IQR: 17-1435) to 998 (IQR: 678-2205) cells/mm3 in adults and children respectively after 12 months of ART. Nevertheless, small but significant number of clinically asymptomatic adults (16%) and children (13%) had low level viraemia (HIV-1 RNA 41-1000 copies/ml). CONCLUSIONS:Majority of both adults (82%) and children (87%) who received ART showed high viral suppression and immunological recovery. This indicates that despite limited resources in the setting virological efficacy can be sustained for a substantial length of time and also enhance immunological recovery irrespective of age. However, the presence of drug resistance mutations and low level viraemia among clinically asymptomatic patients highlights the need for virological monitoring.

Dataset Information

Add-on Pyridostigmine Enhances CD4+ T-Cell Recovery in HIV-1-Infected Immunological Non-Responders: A Proof-of-Concept Study.

Publications

Add-on Pyridostigmine Enhances CD4<sup>+</sup> T-Cell Recovery in HIV-1-Infected Immunological Non-Responders: A Proof-of-Concept Study.

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