Plasma Proteomic Profiling Identifies a Subset of HIV Elite Controllers with Inflammatory Profiles Resembling People Without HIV
- 1Division of HIV, Infectious Diseases, and Global Medicine, UCSF, San Francisco, CA, USA
Abstract
Background: 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. Methods: We measured 384 plasma proteins in ART-naive 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. Results: ART-suppressed non-controllers had higher inflammatory protein levels than ART-naive 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-1{beta}, 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. Conclusions: 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.
Related
- Pre-symptomatic proteomic and metabolomic profiling identifies compensated ER-redox-metabolic adaptation and early nuclear vulnerability in neuronal ERO1L toxicity
- Proteomic profiling of baseline CSF and serum from HDClarity identifies signatures for Huntington disease staging and stratification
- DNA methylation and proteomic profiling of postmortem brain tissue reveals epigenetic dysregulation and inflammatory signaling in fragile X-associated tremor/ataxia syndrome.
- Longitudinal multi-omics profiling of tofacitinib response identifies a pre-existing Janus kinase-tractable inflammatory state in ulcerative colitis
- Proteomic profiling of follicular fluid reflects follicle size and development in Bali cattle (Bos javanicus domesticus)
BibTeX
@misc{falcinelli2026plasma,
title = {{Plasma Proteomic Profiling Identifies a Subset of HIV Elite Controllers with Inflammatory Profiles Resembling People Without HIV}},
author = {S. D. Falcinelli and D. P. Maison and I. Avila-Vargas and T. Dalhuisen and C. Jiang and X. Lian and C. Gao and M.-G. Shin and R. Thomas and J. Feng and J. Salazar and R. Hoh and J. N. Martin and S. P. Deeks and P. W. Hunt and M. Lichterfeld and X. Yu and T. J. Henrich and M. J. Peluso},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.06.749753},
url = {https://www.biorxiv.org/content/10.64898/2026.09.06.749753v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Plasma Proteomic Profiling Identifies a Subset of HIV Elite Controllers with Inflammatory Profiles Resembling People Without HIV
AU - S. D. Falcinelli
AU - D. P. Maison
AU - I. Avila-Vargas
AU - T. Dalhuisen
AU - C. Jiang
AU - X. Lian
AU - C. Gao
AU - M.-G. Shin
AU - R. Thomas
AU - J. Feng
AU - J. Salazar
AU - R. Hoh
AU - J. N. Martin
AU - S. P. Deeks
AU - P. W. Hunt
AU - M. Lichterfeld
AU - X. Yu
AU - T. J. Henrich
AU - M. J. Peluso
PY - 2026
DA - 2026/09/06
PB - bioRxiv
DO - 10.64898/2026.09.06.749753
UR - https://www.biorxiv.org/content/10.64898/2026.09.06.749753v1
AB - Background: 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. Methods: We measured 384 plasma proteins in ART-naive 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. Results: ART-suppressed non-controllers had higher inflammatory protein levels than ART-naive 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-1{beta}, 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. Conclusions: 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.
ER -