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Gut-derived bacterial toxins impair memory CD4(+) T cell mitochondrial function in HIV-1 infection

People living with HIV (PLWH) who are immune nonresponders (INRs) are at greater risk of comorbidity and mortality than are immune responders (IRs) who restore their CD4(+) T cell count after antiretroviral therapy (ART). INRs have low CD4(+) T cell counts (<350 c/μL), heightened systemic inflamm...

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Detalles Bibliográficos
Autores principales: Ferrari, Brian, Da Silva, Amanda Cabral, Liu, Ken H., Saidakova, Evgeniya V., Korolevskaya, Larisa B., Shmagel, Konstantin V., Shive, Carey, Pacheco Sanchez, Gabriela, Retuerto, Mauricio, Sharma, Ashish Arunkumar, Ghneim, Khader, Noel-Romas, Laura, Rodriguez, Benigno, Ghannoum, Mahmoud A., Hunt, Peter P., Deeks, Steven G., Burgener, Adam D., Jones, Dean P., Dobre, Mirela A., Marconi, Vincent C., Sekaly, Rafick-Pierre, Younes, Souheil-Antoine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9057623/
https://www.ncbi.nlm.nih.gov/pubmed/35316209
http://dx.doi.org/10.1172/JCI149571
Descripción
Sumario:People living with HIV (PLWH) who are immune nonresponders (INRs) are at greater risk of comorbidity and mortality than are immune responders (IRs) who restore their CD4(+) T cell count after antiretroviral therapy (ART). INRs have low CD4(+) T cell counts (<350 c/μL), heightened systemic inflammation, and increased CD4(+) T cell cycling (Ki67(+)). Here, we report the findings that memory CD4(+) T cells and plasma samples of INRs from several cohorts are enriched in gut-derived bacterial solutes p-cresol sulfate (PCS) and indoxyl sulfate (IS) that both negatively correlated with CD4(+) T cell counts. In vitro PCS or IS blocked CD4(+) T cell proliferation, induced apoptosis, and diminished the expression of mitochondrial proteins. Electron microscopy imaging revealed perturbations of mitochondrial networks similar to those found in INRs following incubation of healthy memory CD4(+) T cells with PCS. Using bacterial 16S rDNA, INR stool samples were found enriched in proteolytic bacterial genera that metabolize tyrosine and phenylalanine to produce PCS. We propose that toxic solutes from the gut bacterial flora may impair CD4(+) T cell recovery during ART and may contribute to CD4(+) T cell lymphopenia characteristic of INRs.