Distinctive Inflammatory Proteomic Profile of HIV‐1 Elite Controllers: A Comparative Study in a Spanish Cohort

Elite controllers (EC) are people living with HIV (PLWH) able to control HIV replication without antiretroviral therapy and have been proposed as a model of functional cure. Significant evidence suggests that despite viral control, EC subjects may have altered levels of systemic inflammation. We have performed a comprehensive characterization of the systemic inflammation profile in EC compared to non‐controllers PLWH either with or without ART‐mediated control of viral replication. 40 participants were included: 10 EC, 10 non‐controllers PLWH on ART (onART), 10 non‐controllers PLWH ART‐naïve (offART), and 10 uninfected controls (UC) as reference. Plasmatic levels of 92 surrogate markers of inflammation were assessed using the proximity extension assay (Olink proteomics, Sweden). An additional panel of nine proteins was also assayed by comercial ELISA. Differential expression analysis, principal component analysis (PCA), and clustering analysis were carried out using the Metaboanalyst software and the R software. Pathway enrichment analysis (PEA) was carried out using the STRING platform. Compared to UC, offART group showed the highest disturbance in the inflammatory markers with 30 different proteins differentially expressed (DE) (29/30 upregulated; p <0.05). In contrast, onART group presented a profile similar to UC with only 4 proteins DE (3/4 upregulated). Interestingly, EC group presented a more disturbed inflammatory profile than onART group, with 10 different proteins DE with respect to UC group (10/10 upregulated; p <0.05), of which 3 were DE only in EC group. Of note, among these 3 proteins were CCL4 (a ligand for HIV‐correceptor CCR5) and CCL13 (a ligand for HIV‐correceptor CCR2). Regarding clinical status, a substantial comorbidity burden was observed in both groups with controlled viremia (EC and onART), with metabolic and cardiovascular conditions being the most prevalent. Our study shows that HIV control mechanisms, ART‐mediated or spontaneous, are linked to distinct inflammatory profiles. Despite successful viral suppression, both EC and onART individuals maintain persistent inflammatory signatures compared to uninfected controls, which are associated with a significant burden of non‐AIDS comorbidities. These findings underscore the need for clinical monitoring and personalized strategies to mitigate inflammation‐driven morbidity in all PLWH phenotypes.