Occult hepatitis C virus elicits mitochondrial oxidative stress in lymphocytes and triggers PI3-kinase-mediated DNA damage response.

Occult hepatitis C viral infection (OHCI) is a newly reported pathological entity associated with increased risk of developing hepatocellular carcinoma and lymphoproliferative disorders. Although hepatocytes are the primary sites of viral replication, hepatitis C virus is potentially lymphotropic, invading and propagating in cells of the immune system. Lymphocytes, the extrahepatic viral reservoirs, are differentially implicated in the occult and the active forms of the disease. This study aimed to elucidate the implications of mitochondrial oxidative stress on the immune pathophysiological mechanisms of OHCI. We herein report that OHCI induces mitochondrial oxidative stress, leading to DNA double-strand breaks and elicitation of a phosphoinositol 3-kinase-mediated cellular response in peripheral blood lymphocytes. Compared to controls, OHCI subjects showed higher accumulation of pATM, pATR, γH2AX, and p-p53, along with active recruitment of repair proteins (Mre11, Rad50, and Nbs1) and altered mitochondrial DNA content. Increased mitochondrial membrane depolarization and circulating nucleosome levels along with chromatid-type aberrations and decreased T-cell proliferative index observed in the OHCI group further indicated that this damage might lead to Bax-triggered mitochondria-mediated cellular apoptosis. Together our results provide the mechanistic underpinnings of mitochondrial dysfunction in OHCI, a previously unknown paradigm, for explaining the immune pathogenesis in a redox-dependent manner.