Background
A team from Hospital Universitari Germans Trias i Pujol in Spain used Olink® Target 96 Inflammation, Neurology and Neuro-Exploratory panels to characterize proteomic changes in patients enrolled in a phase I clinical trial for HIV-1 cure. Biomarkers predicting the outcome of HIV-1 virus control in natural infection and after therapeutic interventions in HIV-1 cure trials remain poorly defined. The BCN02 trial, combined a T-cell vaccine with romidepsin (RMD), a histone deacetylase inhibitor that was used to promote HIV-1 latency reversal. Samples from trial participants were used to carry out a longitudinal plasma proteomics analyses in to define biomarkers associated with virus control during monitored antiretroviral therapy (ART) pause (MAP) and to identify potential therapeutic targets to improve future cure strategies.
Outcome
Participants were divided based on their ability to control viral levels during MAP: 8 showed a rapid HIV-1 plasma rebound (“MAP-NC”), while 3 maintained plasma virus counts during the withdrawal of ART (“MAP-C”). An integration data analysis (proteomic, viral and neurocognitive parameters) was then performed. Principle component analysis (PCA) was performed on 276 proteins with samples taken at 3 timepoints during the trial. Administration of RMD affected the levels of 49 proteins, while 76 markers were modulated overall during MAP (29 overlapping between the two). In terms of insights into drug action, proteins affected by RMD were mostly associated with “cytokine release by the interaction with viral proteins” (CCL25, CXCL5, IL20RA and IL15) and “innate and cellular adaptive immune response markers” (CD8A and CD38). Proteins affected during MAP were largely associated with pathways linked to cell regulation and cytokine response.
Significant differences were observed for several proteins between MAP-C and MAP-NC patients (including in baseline samples). However, CD33/Siglec-3 was unique in discriminating between MAPC-C and MAP-NC at all study timepoints and showed positive correlations with viral parameters. Further analysis confirmed the positive correlation between viral parameters and CD33 plasma levels in an untreated cohort of people living with HIV, which was supported by CD33 gene expression in circulating monocytes. The relevance of this finding was further strengthened by experiments showing that an anti-CD33 antibody could significantly reduce HIV-1 replication and proviral levels in T cells and macrophages cultured in vitro. Taken together, these findings suggest that CD33 is a potentially important biomarker for HIV-1 control and worthy of further study.
