Background:
The discovery of biomarkers that predict viral rebound after ATI would significantly contribute to the HIV cure field. Further, the discovery of biomarkers predicting viral rebound after ART discontinuation will inform and guide ATI studies to understand who is more likely to experience a viral rebound and could help select participants for ART interruption studies to make ART discontinuation safer and more effective.
Methods:
We initiated a multi-center, open-label trial of three monthly intravenous (IV) administration of 20 mg/kg each of PGT121, PGDM1400, and VRC07-523LS (n=12) in persons living with HIV-1 (PLWH) following discontinuation of antiretroviral therapy (ART). ART was interrupted 2 days after the first broadly neutralizing monoclonal antibodies (bNAb) infusion. We collected plasma from all participants two days before ATI, multiple times off ART, and after rebound. We conducted high-throughput transcriptomics, proteomics, and metabolomics at all time points in all participants.
Results:
We investigated protein signatures modulated after ATI, before detectable rebound (VL< 200cp/ml), and after rebound (VL>200cp/ml) compared with baseline (pre-ATI). We observed a significant increase (FDR q value < 0.05) of T cells, immune activation, and proinflammatory signatures preceding detectable rebound (VL<200 cp/ml) that were augmented after rebound. Signatures of activated proinflammatory macrophage M1, response to interferon-alpha and gamma as well as proinflammatory cytokines and chemokines (CXCL10, CXCL9, TNFRSF1B, CD14, CSF1) were elevated before detectable rebound compared with pre-ATI. Metabolic pathways show dysregulation or a decrease after analytical treatment interruption (ATI) and before detectable rebound, indicating metabolic changes associated with the rebound virus (Fig 1).
Conclusions:
Our preliminary observations highlight the role of proinflammatory signatures and macrophages as potential plasma biomarkers to predict imminent rebound following ATI.
