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2-hydroxypropyl-beta-cyclodextrin treatment induces modest immune activation in healthy rhesus macaques [RNA-seq]

ABSTRACT: Experimental SIV infection of Asian macaques is an excellent model for HIV disease progression and therapeutic development. Recent coformulations of nucleoside analogs and an integrase inhibitor have been used for parenteral antiretroviral (ARV) administration in SIV-infected macaques, successfully resulting in undetectable plasma SIV RNA. In a cohort of SIVmac239-infected macaques, we recently observed that administration of co-formulated ARVs resulted in an unexpected increase in plasma levels of soluble CD14 (sCD14), associated with stimulation of myeloid cells. We hypothesized that the coformulation solubilizing agentKleptoseTM(2-hydroxypropyl-beta-cyclodextrin; HPβCD) may induce inflammation with myeloid cell activation and the release of sCD14. Herein, we stimulated peripheral blood mononuclear cells (PBMCs) from healthy macaques with HPβCD from different commercial sources and evaluated inflammatory cytokine productionin vitro.Treatment of PBMCs resulted in increased sCD14 release and myeloid cell IL-1bproduction - with stimulation varyingsignificantlyby HPβCD source - and destabilized lymphocyte CCR5 surface expression.We further treated healthy macaques withKleptosealone.In vivo, we observed modestly increased myeloid cell activation in response to Kleptose treatment without significant perturbation of the immunological transcriptome or epigenome.Our resultsdemonstrate a need for vehicle-only controls and highlight immunological perturbations that can occur when using HPβCD in pharmaceutical co-formulations.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE233466 | GEO | 2023/06/12

REPOSITORIES: GEO

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2-hydroxypropyl-beta-cyclodextrin treatment induces modest immune activation in healthy rhesus macaques [ATAC-seq]

Project description:Experimental SIV infection of Asian macaques is an excellent model for HIV disease progression and therapeutic development. Recent coformulations of nucleoside analogs and an integrase inhibitor have been used for parenteral antiretroviral (ARV) administration in SIV-infected macaques, successfully resulting in undetectable plasma SIV RNA. In a cohort of SIVmac239-infected macaques, we recently observed that administration of co-formulated ARVs resulted in an unexpected increase in plasma levels of soluble CD14 (sCD14), associated with stimulation of myeloid cells. We hypothesized that the coformulation solubilizing agentKleptoseTM(2-hydroxypropyl-beta-cyclodextrin; HPβCD) may induce inflammation with myeloid cell activation and the release of sCD14. Herein, we stimulated peripheral blood mononuclear cells (PBMCs) from healthy macaques with HPβCD from different commercial sources and evaluated inflammatory cytokine productionin vitro.Treatment of PBMCs resulted in increased sCD14 release and myeloid cell IL-1bproduction - with stimulation varyingsignificantlyby HPβCD source - and destabilized lymphocyte CCR5 surface expression.We further treated healthy macaques withKleptosealone.In vivo, we observed modestly increased myeloid cell activation in response to Kleptose treatment without significant perturbation of the immunological transcriptome or epigenome.Our resultsdemonstrate a need for vehicle-only controls and highlight immunological perturbations that can occur when using HPβCD in pharmaceutical co-formulations.

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