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

Chronic IL-1{beta}-driven inflammation contributes to cardiovascular risk and potentially HIV reservoir persistence in people with HIV (PWH) but the effects of direct IL-1{beta} blockade have not been defined. We show that canakinumab, an anti-IL-1{beta} monoclonal antibody, induces a unique set of genes (Cana_Up) and suppresses a unique set of genes (Cana_Down) in whole blood sequencing that are both associated with reduced HIV reservoir. We validated the association of Cana_Up genes with low reservoir in an independent dataset. Cana_Up genes are expressed mainly by CD4 and CD8 T cells and map to pathways of cell cycling (Myc, E2F, G2M) and antigen presentation. Th17 cells in the blood and tissue resident HIV reservoir in the gut express pathways targeted by canakinumab to reduce reservoir. Participants with reduced reservoir after canakinumab show enhanced HIV-specific CD4 and CD8 effector function. Cana_Down genes are expressed the highest by CD14+ monocytes, which are a confirmed source of IL-1b in our study, and map to inflammatory pathways (NF-kB, RELA) and PRC1/2 complex members that regulate epigenetics (EZH2, JARID2). These findings establish a mechanistic rationale for IL-1{beta} blockade as an immune reconditioning strategy in HIV that can reverse monocyte driven inflammatory dysfunction and enhance HIV-specific CD4 and CD8 effector responses to effectively target the HIV reservoir.