Background:
HIV cure strategies will require the elimination of latently HIV infected cells from all sites of the viral reservoir, including central nervous system. Latency reversing agents (LRA) that can reach all these sites may thus be needed. The BCN02 trial (NCT02616874) combined the HIVconsv T-cell vaccine with the latency reversing agent romidepsin (RMD), a LRA that also has been linked to beneficial effects in neurological diseases. To identify biomarkers associated with virus control during monitored antiretroviral pause (MAP), longitudinal proteomics screenings were conducted in plasma from BCN02 participants.
Methods:
Plasma proteomes of longitudinal samples from 11 BCN02 participants, including 8 MAP-non controllers (MAP-NC, viral loads >2000 copies/ml < 4 weeks) and 3 MAP-controllers (MAP-C, viral load < 2000 copies/ml for >32 weeks) were determined. Integration data analysis (viral load, proviral levels, and neurocognitive assessments) was performed to identify candidates. For validation, untreated chronically HIV infected individuals (n=96) with different levels of virus control were included. Finally, in vitro viral replication assays and proviral quantification targeting CD33 in PHA-stimulated T-cells and macrophages derived monocytes were performed.
Results:
During the BCN02 trial, plasma proteomes changed longitudinally, with most changes observed after RMD infusions and during MAP and significant differences between MAP-C and MAP-NC were observed already before the initiation of the intervention. CD33 protein was uniquely increased upon RMD administration and maintained during MAP and allowed to discriminate between MAP-C and MAP-NC, even when assessed before RMD treatment. CD33 plasma levels were positively associated with viral load and proviral levels in the BCN02 trial. Validation untreated chronically HIV infected individuals showed higher plasma levels of CD33 associated with reduced virus control. While neurocognitive assessments did not correlate with CD33 plasma levels in the BCN02 trial, positive correlations between CD33 protein and neurofilament light protein were observed after RMD administration and during MAP. In vitro targeting of CD33 showed reduced HIV replication and proviral levels, suggesting an important role of CD33 in the HIV life cycle.
Conclusions:
This study identifies CD33 as key factor associated with virus control post Kick-and-Kill intervention and in natural HIV infection. Targeting CD33 may be considered for future HIV therapeutic cure strategies.