Genome-scale metabolic models for natural and long-term drug-induced viral control in HIV infection.
Anoop T AmbikanSara Svensson AkusjärviShuba KrishnanMaike SperkPiotr NowakJan VesterbackaAnders SönnerborgRui BenfeitasUjjwal NeogiPublished in: Life science alliance (2022)
Genome-scale metabolic models (GSMMs) can provide novel insights into metabolic reprogramming during disease progression and therapeutic interventions. We developed a context-specific system-level GSMM of people living with HIV (PLWH) using global RNA sequencing data from PBMCs with suppressive viremia either by natural (elite controllers, PLWH EC ) or drug-induced (PLWH ART ) control. This GSMM was compared with HIV-negative controls (HC) to provide a comprehensive systems-level metabo-transcriptomic characterization. Transcriptomic analysis identified up-regulation of oxidative phosphorylation as a characteristic of PLWH ART , differentiating them from PLWH EC with dysregulated complexes I, III, and IV. The flux balance analysis identified altered flux in several intermediates of glycolysis including pyruvate, α-ketoglutarate, and glutamate, among others, in PLWH ART The in vitro pharmacological inhibition of OXPHOS complexes in a latent lymphocytic cell model (J-Lat 10.6) suggested a role for complex IV in latency reversal and immunosenescence. Furthermore, inhibition of complexes I/III/IV induced apoptosis, collectively indicating their contribution to reservoir dynamics.
Keyphrases
- drug induced
- liver injury
- antiretroviral therapy
- hiv infected
- induced apoptosis
- single cell
- hiv positive
- human immunodeficiency virus
- hiv aids
- oxidative stress
- rna seq
- sars cov
- signaling pathway
- hepatitis c virus
- physical activity
- body composition
- cell therapy
- mesenchymal stem cells
- magnetic resonance imaging
- stem cells
- south africa
- gene expression
- data analysis