Background
Elite Controllers (EC) are a model for HIV cure research, maintaining durable viral suppression without ART through unique immune responses. The microbiome could regulate HIV-specific responses in EEC by affecting inflammation and antiviral immunity.
Methods
We established a cohort of exceptional EC (EEC, >10 years HIV control without ART, VL <50 copies/mL, CD4 nadir >350/µL) and chronic progressors (CP, PWH on ART, undetectable VL, CD4 nadir <350/µL), matched for age, sex, and sexual orientation. Plasma levels of 364 inflammatory proteins were profiled (Olink®) and markers identified with mixOmics. Stool metagenomes were analyzed for taxonomy (mOTUs3) and function (eggNOG-mapper). Inactivated fecal bacterial communities (FBC) and sterile filtrates (SF) were prepared. CP’s PBMCs were primed with SF or FBC, stimulated with HIV peptides, and gene expression of 9 genes was quantified by qPCR.
Results
We studied 37 EEC (mean 27 years of control, CD4 568/µL, CD4/CD8 ratio 1.0) and 33 CP, without differences in cardiovascular risk or comorbidities. Metagenomic analyses showed enrichment of Lactococcus lactis, Parabacteroides johnsonii, Clostridium spp., Paraprevotella clara, and Dialister invisus in EEC, with depletion of Bacteroides and Veillonella. Functional profiling revealed in EEC reduced representation of toxin and stress metabolism genes (CdtB, nitrate/nitrite transport, heme synthesis) and enrichment of regulatory, carbohydrate, and structural pathways, including hemolysins, suggesting lower virulence but greater metabolic adaptability.
Plasma proteomics identified a 15-protein signature, including IL32, IL16, IL18, CCL2, CCL3, CCL4, CCL22, CXCL9, and STX8, with IL32 and CCL3 validated in vitro. In stimulation assays, HIV peptides induced all genes assessed. Preconditioning with SF from EEC or CP blunted NLRP3 and CASP1 compared with FBC, indicating strong effects of soluble metabolites. Group-specific differences emerged: SF-EC attenuated NLRP3 downregulation, while IL2 was more strongly suppressed than with SF-CP.
Conclusions
EEC showed distinct host–microbiome signatures, antiviral markers, enrichment of metabolic taxa, and fewer virulence functions. Microbial preparations from EEC primed a less pro-inflammatory state, whereas those from CP likely delivered more PAMPs and inflammatory metabolites, reprogramming inflammasome pathways. These findings suggest the microbiome supports long-term HIV control in EEC by restraining inflammation while preserving antiviral capacity.
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