Vpr attenuates antiviral immune responses and is critical for full pathogenicity of SIVmac239 in rhesus macaques
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ABSTRACT:
PROVIDER: PRJNA953997 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24119600.fastq.gz | Fastqsanger.gz | |||
| SRR24119700.fastq.gz | Fastqsanger.gz | |||
| SRR24119800.fastq.gz | Fastqsanger.gz | |||
| SRR24119900.fastq.gz | Fastqsanger.gz | |||
| SRR24119601.fastq.gz | Fastqsanger.gz |
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Project description:The accessory viral protein R (Vpr) is encoded by all primate lentiviruses. Vpr counteracts DNA repair pathways, modulates viral immune sensing, and induces cell-cycle arrest in cell culture. However, its impact in vivo is controversial. Here, we show that deletion of vpr is associated with delayed viral replication kinetics, rapid innate immune activation, development and maintenance of strong B and T cell responses, and increased neutralizing activity against SIVmac239 in rhesus macaques. All wild-type SIVmac239-infected animals maintained high viral loads, and five of six developed fatal immunodeficiency during ∼80 weeks of follow-up. Lack of Vpr was associated with better preservation of CD4+ T cells, lower viral loads, and an attenuated clinical course of infection in most animals. Our results show that Vpr contributes to efficient viral immune evasion and the full pathogenic potential of SIVmacin vivo. Inhibition of Vpr may improve humoral immune control of viral replication.
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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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