Background
Following antiretroviral treatment (ART) interruption, people living with HIV (PLWH) exhibit diverse rebound kinetics including time to rebound, rebound slope, and control of viremia. To test if these differences are driven by the initial host immune response to rebounding virus, we conducted a highly sampled analytical treatment interruption (ATI) study focused on the time after ART levels are expected to have waned and before the virus was detectable.
Methods
We assayed peripheral blood mononuclear cells (PBMC) and plasma collected longitudinally on ART and during ATI(median 15 samples assayed per donor). We analyzed transcriptomic, proteomic, and high dimensional flow cytometric data. Bulk RNAseq data (DESeq2 normalized, controlled for donor and batch) was used to identify differentially expressed genes (FDR<0.05, l2FC>±0.5) and assess gene set enrichment. Paired Wilcoxon tests, and piecewise linear regression were used to identify and model cell subset and soluble protein changes.
Results
We enrolled prior Viremic Controllers and Non-Controllers (75% cis men, 70% white, 95% subtype B, VC n=7, NC n=13). Compared to NC, VC had a longer time to rebound (median VC=40 days, NC=17 days, p<0.01) and a slower rate of rebound (p<0.01). Across donors, antiviral genes including FCGR1A/3A/3B, IFIT1/2/3, MX1/2, OAS1/2/3, and STAT1 (the “early rebound response pathway”, ERRP) were upregulated post-ART and prior to detectable rebound (ρ=0.67, p<0.01). Antiviral CD16++ monocytes (p=0.02) also increased before detectable rebound in both groups. Inflammatory cytokines downstream of ERRP genes – including IFNA1/13, IFNL1, IL12p70, CXCL10, and LAG3 – increased just prior to rebound (ρ=0.57, p<0.01). Compared to VC, NC had enriched ERRP expression while on ART (FDR<0.01). During ATI, VC mounted immune responses earlier than NC: in VC, innate immune pathways became enriched >7 days before rebound; adaptive pathways became enriched ≤7 days of rebound. While NC showed transcriptional changes, immune pathways were not significantly enriched (compared to on-ART) until post-rebound. Post-rebound, ERRP expression was higher in NC than VC (FDR<0.01).
Conclusions
With high resolution sampling, we investigated the earliest post-ART virus:immune interaction. The initial host response to rebounding HIV is distinct in people who experience typical progression from those who control. These pathways could provide biomarkers that predict future rebound and/or might be targeted in future cure strategies.
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