Novel Anti-Retroviral Drug Targets: Interfering siRNA and Mitochondrial TERT Expression

Abstract

Telomerase can be touted as the miracle anti-aging enzyme that reverses the age-related attrition of telomere ends. The catalytic subunit of telomerase, TERT telomerase reverse transcriptase, is known to function as an RNA dependent DNA polymerase in the nucleus (TERT-TERC), as an RNA dependent RNA polymerase, an RdRP (TERT-RMRP), in mitochondria, and, as TERT alone interacting with master regulators for cell and organellar protection to promote global survival and rejuvenation potential. TERT shows conservation of the viral polymerase structure, and like viral polymerases, is capable of producing cDNA, double stranded RNA, and like HIV reverse transcriptase, is inhibited by some HIV reverse transcriptase inhibitors. TERT also shows promiscuous partnering with RNA elements, RMPR, tRNA, and TERC. TERT, with its versatile viral-like functions, seems like a valuable hostage for viral infection. Telomerase is inhibited by viral proteins. When the role of telomerase in HIV infection is reviewed, telomerase modulation emerges as a valuable player in HIV therapy intervention. Induced viral protein and some reverse transcriptase HIV drugs promote TERT deficit which might be counteracted by TERT up regulation, or preference for use of drugs that do not target host reverse transcriptase, in order to preserve the health promotion of TERT pathways especially mitochondrial protection against oxidative stress, and inhibition of pathways that promote immune deficiency. Telomerase "dark side" dysfunctional overexpression might be targeted using an anti-cancer-like vaccine, delivered selectively to viral reservoirs. The use of siRNA's to inactivate proteins that promote viral survival offer promising potential success in anti-retroviral therapy, with the ability to block mico RNAs favorable for viral progression. Strategies and therapy that interfere with the HIV-TAR interaction offer the desirable ability to stop infection before it starts. Mimetics of exercise, hibernation, anti-aging supplements, and mitochondrial targeted antioxidants offer antiviral potential and disease vulnerability from fallout of immune deficiency. SchramlE, Grillari J (2012) From cellular senescence to age-associated diseases: the miRNA connection. Longev Healthspan 1: 10. 76. Bai XY, Ma Y, Ding R, Fu B, Shi S, et al. (2011) miR-335 and miR-34a Promote renal senescence by suppressing mitochondrial antioxidative enzymes. J Am Soc Nephrol 22: 1252-1261. Citation: Smith-Sonneborn J (2016) Novel Anti-Retroviral Drug Targets: Interfering siRNA and Mitochondrial TERT Expression. Virol-mycol 5: 150.

Epigenetic Treatment of Persistent Viral Infections

“…Nrf2 (encoded by Nfe2l2) is a transcription factor responsible for the regulation of cellular redox balance and protective antioxidant and phase II detoxification responses in mammals [Limongi and Baldelli, 2016;Loboda et al, 2016]. Some reports suggest that ALA (a potent activator of Nrf2 [Prasad, 2015[Prasad, , 2016 and an NF-jB inhibitor [Ying et al, 2011;Rochette et al, 2015]) taken with carnitine supplements helps initiate protective metabolic networks and enhance health and disease resistance [Smith-Sonneborn, 2016]. For therapeutic indications, however, ALA and butyrate (also an Nrf2 activator [Vahid et al, 2015] and an NF-jB inhibitor [Bail on et al, 2010;Canani et al, 2011;Galland, 2014;Stilling et al, 2016]) are effectively precluded from clinical use due to poor pharmacokinetic and metabolic properties (short half-lives and first-pass hepatic clearance) in vivo [Steliou et al, 2012].…”