Background
Beyond their neutralization activity, bNAbs may enable post-treatment control of HIV by promoting effective endogenous HIV-specific immune responses via HIV:bNAb immune complexes (the vaccinal effect). In the UCSF-amfAR combination immunotherapy trial (NCT04357821), 10 participants with HIV on antiretroviral therapy (ART) received interventions including infusions of two bNAbs (10-1074 & VRC07-523LS), the second just before stopping ART (analytic treatment interruption [ATI]). 7 participants controlled HIV to varying degrees despite bNAbs waning. We looked for evidence of immune activation during bNAb-mediated HIV suppression following ATI.
Methods
We performed CyTOF (cellular phenotypes), CITE-Seq (single cell RNA sequencing with protein expression), NULISAseq (plasma proteins), and the Replicate Aptima Assay (single copy plasma viral load) on peripheral blood samples from 2 timepoints: within a week prior to ATI (preATI) and 1-2 months post-ATI/bNAbs (>28 days before quantifiable rebound as detected by clinical assays; early bNAb). Statistical comparisons included paired t-tests (CyTOF and NULISAseq) and Gene Set Enrichment Analysis on cell subpopulations with Benjamini-Hochberg false discovery rate correction (CITE-Seq).
Results
Despite nearly undetectable plasma HIV RNA levels (0-1 copy/mL) at the early bNAb timepoint, several findings suggested increased immune activation compared to preATI. The fraction of conventional dendritic cells (cDC1s) and monocytes expressing the maturation marker CD40 increased (CyTOF: median 20.1% to 27.6%, 14.0% to 23.7% respectively; p<0.05). Pathways associated with innate antiviral signaling (e.g. type I interferons, IL-1b, TNFa) were more enriched in plasmacytoid (p)DCs, cDC2s, and NK cells at the early bNAb timepoint (CITE-Seq: adjusted p<0.05; Figure). Finally, there was an increase in plasma proteins involved in antigen presentation, inflammatory cytokine signaling, and immune cell trafficking (NULISAseq: DC-LAMP, IL18R1, CCL21; p<0.05).
Conclusions
In this study, HIV suppression by bNAbs – as compared to ART – was associated with an increase in immune activation, particularly in innate immune cells, weeks to months before quantifiable rebound. These findings may reflect low-level viral replication in tissues during bNAb-mediated suppression, which may in turn stimulate HIV-specific immune responses directly and/or via HIV:bNAb immune complexes. The impact of bNAbs on the reservoir and long-term control of HIV remain to be defined.
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