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

Area of Science:

• Immunology
• Microbiology
• HIV/AIDS Research

Background:

• People living with HIV (PLWH) who are immune nonresponders (INRs) exhibit low CD4+ T cell counts, heightened inflammation, and increased T cell cycling.
• Immune responders (IRs) restore CD4+ T cell counts with antiretroviral therapy (ART), unlike INRs.

Purpose of the Study:

• To investigate the role of gut-derived bacterial solutes in the impaired CD4+ T cell recovery observed in INRs.

Main Methods:

• Analysis of memory CD4+ T cells and plasma from INR and IR cohorts.
• In vitro studies assessing the effects of p-cresol sulfate (PCS) and indoxyl sulfate (IS) on CD4+ T cells.
• Electron microscopy to examine mitochondrial morphology.
• Bacterial 16S rDNA sequencing of stool samples from INRs.

Main Results:

• INR samples showed enrichment of gut-derived PCS and IS, which negatively correlated with CD4+ T cell counts.
• In vitro, PCS and IS inhibited CD4+ T cell proliferation, induced apoptosis, and reduced mitochondrial protein expression.
• Electron microscopy revealed mitochondrial network damage in CD4+ T cells exposed to PCS.
• INR stool samples were enriched in proteolytic bacteria producing PCS.

Conclusions:

• Toxic gut bacterial solutes, PCS and IS, may hinder CD4+ T cell recovery during ART in INRs.
• These solutes may contribute to the characteristic CD4+ T cell lymphopenia in INRs.
• Targeting gut microbiota metabolism could be a therapeutic strategy for improving immune responses in INRs.