Plasma Proteomic Profiling Identifies a Subset of HIV Elite Controllers with Inflammatory Profiles Resembling People Without HIV.

Authors

Shane D Falcinelli, David P Maison, Isaac Avila-Vargas, Thomas Dalhuisen, Chenyang Jiang, Xiaodong Lian, Ce Gao, Min-Gyoung Shin, Reuben Thomas, Jean Feng, James Salazar, Rebecca Hoh, Jeffrey N Martin, Steven G Deeks, Peter W Hunt, Mathias Lichterfeld, Xu Yu, Timothy J Henrich, Michael J Peluso

Published in

bioRxiv : the preprint server for biology. Sep 13, 2026. Epub Sep 13, 2026.

Abstract

Elite controllers (ECs) are people with HIV (PWH) who suppress viral replication without antiretroviral therapy (ART). A subset, often termed exceptional elite controllers (EECs), harbor very small viral reservoirs, with few intact proviruses integrated into inactive chromosomal regions. Defining inflammatory signatures in ECs may clarify whether some approach a functionally cured state.
We measured 384 plasma proteins in ART-naïve ECs (n=62), ART-suppressed non-controllers (n=37), and people without HIV (PwoH) (n=50) using Olink proteomics, and compared proteomic profiles, clinical parameters, and intact reservoir data using FLIP-Seq. Hierarchical clustering identified ECs whose proteomic profiles most closely resembled PWoH; this subset was further analyzed using machine-learning approaches.
ART-suppressed non-controllers had higher inflammatory protein levels than ART-naïve ECs, yet ECs still showed elevated inflammation and lower CD4:CD8 ratios compared with PWoH. Clustering analysis revealed a distinct subset of ECs (n=9) whose profiles closely matched those without HIV (ECs with PWoH-like proteomic profiles), a pattern not observed in ART-suppressed non-controllers. Compared to typical ECs, ECs with PWoH-like proteomic profiles had consistently lower IL-1β, SCRN1, and BID, numerically lower intact proviral frequencies, and a high frequency of protective HLA alleles. Machine-learning analyses highlighted features that most strongly differentiated ECs with PWoH-like proteomic profiles from typical ECs, including reduced gut mucosal/intestinal epithelial-associated proteins, higher absolute CD4 counts, and lower levels of pro-inflammatory cytokines and cellular immune activation.
These findings identify a subset of ECs with a PWoH-like inflammatory proteomic profile, accompanied by numerically lower intact HIV reservoirs and a high frequency of protective HLA alleles. Defining the mechanisms associated with this low-inflammatory state may provide insights into exceptional HIV control and inform strategies for durable HIV remission.

PMID:
42818707
Bibliographic data and abstract were imported from PubMed on 01 Oct 2026.

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