RT Journal Article
SR Electronic
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
FD Life Science Alliance LLC
SP e202201405
DO 10.26508/lsa.202201405
VO 5
IS 9
A1 Anoop T Ambikan
A1 Sara Svensson-Akusjärvi
A1 Shuba Krishnan
A1 Maike Sperk
A1 Piotr Nowak
A1 Jan Vesterbacka
A1 Anders Sönnerborg
A1 Rui Benfeitas
A1 Ujjwal Neogi
YR 2022
UL https://www.life-science-alliance.org/content/5/9/e202201405.abstract
AB 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.