Genome-scale metabolic models for natural and long-term drug-induced viral control in HIV infection

Abstract

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, PLWHEC) or drug-induced (PLWHART) 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 PLWHART, differentiating them from PLWHEC 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 PLWHART. 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.

Multi-omics personalized network analyses highlight progressive disruption of central metabolism associated with COVID-19 severity

“…We also reported that by blocking two critical central metabolic pathways, glycolysis and glutaminolysis, viral replication and production were inhibited (Krishnan et al, 2021). Although systemic GSMM was not reported in other respiratory diseases caused by viruses, in our recent study to understand the natural control of HIV-1 infection, we observed the regulation of similar metabolic pathways, but the difference in the metabolic reactions potentiates a disease-specific contextualization of the metabolic flux (Ambikan et al, 2022). A viral disease-specific systemic GSMM atlas for other emerging and re-emerging viruses is underway.…”

Biological Aging in People Living with HIV on Successful Antiretroviral Therapy: Do They Age Faster?

“…We also developed a context-specific system-level Genome-Scale Metabolic Model (GSMM) using global RNA sequencing data on blood cells from PLWH that had suppressive viremia by natural mechanisms (EC) or drug-induced suppression (PLWH on cART) [81]. To provide a comprehensive system-level characterization, this GSMM was also compared to HIV-negative controls.…”

Contemporary Antiretroviral Therapy Dysregulates Iron Transport and Augments Mitochondrial Dysfunction in HIV-Infected Human Microglia and Neural-Lineage Cells

“…Recent gene-expression studies have indirectly evaluated the effects of cART, however: transcriptomic profiles of peripheral blood mononuclear cells (PBMCs) from PWH on suppressive cART may differ significantly from the PBMC profiles in elite HIV controllers, who are naturally virally suppressed without treatment. These transcriptomic studies suggest that inhibition of mitochondrial oxidative phosphorylation contributes to a larger reservoir size during cART [65][66][67]. The changes observed in non-controllers include upregulated glycolysis and glutaminolysis, which are proposed to contribute to accelerated senescence in latently infected immune cells during cART.…”