TY - JOUR T1 - Genome-scale metabolic models for natural and long-term drug-induced viral control in HIV infection JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202201405 VL - 5 IS - 9 SP - e202201405 AU - Anoop T Ambikan AU - Sara Svensson-Akusjärvi AU - Shuba Krishnan AU - Maike Sperk AU - Piotr Nowak AU - Jan Vesterbacka AU - Anders Sönnerborg AU - Rui Benfeitas AU - Ujjwal Neogi Y1 - 2022/09/01 UR - https://www.life-science-alliance.org/content/5/9/e202201405.abstract N2 - 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. ER -