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

Ambikan AT, Svensson-Akusjärvi S, Krishnan S, Sperk M, Nowak P, Vesterbacka J, Sönnerborg A, Benfeitas R, Neogi U

Life Sci. Alliance 5 (9) - [2022-09-00; online 2022-05-10]

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.

Bioinformatics Support for Computational Resources [Service]

PubMed 35537851

DOI 10.26508/lsa.202201405

Crossref 10.26508/lsa.202201405

pii: 5/9/e202201405
pmc: PMC9095731
figshare: 10.6084/m9.figshare.19747582