Therapeutic blockade of IL-1β in PWH reduced the HIV reservoir via mechanisms of enhanced CD8 and CD4 effector function and reversal of monocyte dysfunction
- 1University of California at San Francisco
Abstract
Chronic IL-1{beta}-driven inflammation contributes to cardiovascular risk and potentially HIV reservoir persistence in people with HIV (PWH); the effects of direct IL-1{beta} blockade on HIV persistence have not been defined. We show in a cohort of PWH that canakinumab, an anti-IL-1{beta} monoclonal antibody, is associated to the upregulation (Cana_Up) or the downregulation (Cana_Down) of unique sets of genes that are both associated with reduced HIV reservoir. Cana_Up genes are expressed mostly by CD4 and CD8 T cells and mapped to pathways of cell cycling (Myc, E2F, G2M) and Antigen Cross-Presentation. Th17 cells in the blood and gut tissue require IL-1 to differentiate and concomitantly express pathways reduced by canakinumab that lead to reduced reservoir. Participants with reduced reservoir after canakinumab showed significant enhancement of HIV-specific CD4 and CD8 effector function with increased frequencies of cells expressing the effector proteins IFN{gamma} and Granzyme B and the marker of degranulation CD107a. CD14+ monocytes with the highest level of IL-1{beta} also expressed the highest levels of Cana_Down genes that included inflammatory pathways (NF-kB, RELA) and PRC1/2 complex members that regulate epigenetic mediated closure of chromatin (EZH2, JARID2). These findings establish a mechanistic rationale for IL-1{beta} blockade as a therapeutic intervention that effectively target the HIV reservoir by restoring functional HIV specific adaptive immune responses and reversing monocyte driven inflammatory dysfunction.
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BibTeX
@misc{sharma2026therapeutic,
title = {{Therapeutic blockade of IL-1β in PWH reduced the HIV reservoir via mechanisms of enhanced CD8 and CD4 effector function and reversal of monocyte dysfunction}},
author = {A. A. Sharma and M. Dropathi and N. Sadek and D. Li and A. K. Dwivedi and D. Siegel and R. Rutishauser and S. Deeks and P. Hsue and S. Lee and R. P. Sekaly and J. A. Tomalka},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.11.26362694},
url = {https://www.medrxiv.org/content/10.64898/2026.09.11.26362694v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Therapeutic blockade of IL-1β in PWH reduced the HIV reservoir via mechanisms of enhanced CD8 and CD4 effector function and reversal of monocyte dysfunction
AU - A. A. Sharma
AU - M. Dropathi
AU - N. Sadek
AU - D. Li
AU - A. K. Dwivedi
AU - D. Siegel
AU - R. Rutishauser
AU - S. Deeks
AU - P. Hsue
AU - S. Lee
AU - R. P. Sekaly
AU - J. A. Tomalka
PY - 2026
DA - 2026/09/11
PB - medRxiv
DO - 10.64898/2026.09.11.26362694
UR - https://www.medrxiv.org/content/10.64898/2026.09.11.26362694v1
AB - Chronic IL-1{beta}-driven inflammation contributes to cardiovascular risk and potentially HIV reservoir persistence in people with HIV (PWH); the effects of direct IL-1{beta} blockade on HIV persistence have not been defined. We show in a cohort of PWH that canakinumab, an anti-IL-1{beta} monoclonal antibody, is associated to the upregulation (Cana_Up) or the downregulation (Cana_Down) of unique sets of genes that are both associated with reduced HIV reservoir. Cana_Up genes are expressed mostly by CD4 and CD8 T cells and mapped to pathways of cell cycling (Myc, E2F, G2M) and Antigen Cross-Presentation. Th17 cells in the blood and gut tissue require IL-1 to differentiate and concomitantly express pathways reduced by canakinumab that lead to reduced reservoir. Participants with reduced reservoir after canakinumab showed significant enhancement of HIV-specific CD4 and CD8 effector function with increased frequencies of cells expressing the effector proteins IFN{gamma} and Granzyme B and the marker of degranulation CD107a. CD14+ monocytes with the highest level of IL-1{beta} also expressed the highest levels of Cana_Down genes that included inflammatory pathways (NF-kB, RELA) and PRC1/2 complex members that regulate epigenetic mediated closure of chromatin (EZH2, JARID2). These findings establish a mechanistic rationale for IL-1{beta} blockade as a therapeutic intervention that effectively target the HIV reservoir by restoring functional HIV specific adaptive immune responses and reversing monocyte driven inflammatory dysfunction.
ER -