Gut microbiome signatures linked to HIV-1 reservoir size and viremia control

Background: The potential role of the gut microbiome as a predictor of immune-mediated HIV-1 control in the absence of antiretroviral therapy (ART) is still unknown. In the BCN02 clinical trial, which combined the MVA.HIVconsv immunogen with the latency-reversing agent romidepsin in early-ART treated HIV-1 infected individuals, 23% (3/13) of participants showed sustained low-levels of plasma viremia during 32 weeks of a monitored ART pause (MAP). Here, we present a multi-omics analysis to identify compositional and functional gut microbiome patterns associated with HIV-1 control in the BCN02 trial. Results: Viremic controllers during the MAP (controllers) exhibited higher Bacteroidales/Clostridiales ratio and lower microbial gene richness before vaccination and throughout the study intervention when compared to non-controllers. Longitudinal assessment indicated that the gut microbiome of controllers was enriched in pro-inflammatory bacteria and depleted in butyrate-producing bacteria and methanogenic archaea. Functional profiling also showed that metabolic pathways related to fatty acid and lipid biosynthesis were significantly increased in controllers. Fecal metaproteome analyses confirmed that baseline functional differences were mainly driven by Clostridiales. Participants with high baseline Bacteroidales/Clostridiales ratio had increased pre-existing immune activation-related transcripts. The Bacteroidales/Clostridiales ratio as well as host immune-activation signatures inversely correlated with HIV-1 reservoir size. Conclusions: The present proof-of-concept study suggests the Bacteroidales/Clostridiales ratio as a novel gut microbiome signature associated with HIV-1 reservoir size and immune-mediated viral control after ART interruption. Video abstract

Impact of HIV kick-and-kill therapy on host epigenetic and transcriptional programs in PBMC, and viral rebound after cART interruption

Background: BCN02 was a pilot kick-and-kill clinical trial that combined therapeutic vaccination (MVA.HIVconsv) with the latency reversing agent romidepsin (RMD) followed by a monitored antiretroviral pause (MAP) in 15 early-treated HIV+ individuals (NCT02616874). Out of 12 evaluable participants for an omics subanalysis, 8 participants showed early (pVL > 2000 copies/mL 2000 copies/mL > 4 weeks) in MAP. Systems biology analyses identified epigenetic and molecular mechanisms associated with response to vaccination and RMD and viral rebound kinetics