Development of 2′-Deoxy-4′-C-Ethynyl-2-Fluoroadenosine (EFdA) which has Supremely High Anti-HIV Activity and Low Toxicity and Prevents the Emergence of Resistant HIV Mutants, and Discovery of Different Substrate Selectivity between Viral and Human Nucleic Acid Polymerases

Abstract

Highly Active Antiretroviral Therapy (HAART) has significantly reduced AIDS-related morbidity and mortality. However the prevalence of HIV-1-Associated Neurocognitive Disorders (HAND) has been on the rise in the post-HAART era. A majority of the side effects of HAART can in part at least be attributed directly, or indirectly, to mitochondrial dysfunction. Indeed the rapid early clinical phase-in of HAART required dose de-escalations secondary to toxicities suggested to be related to drug side effects affecting mitochondria. Central to central nervous system (CNS) function is the amyloid precursor protein (APP), the parent protein from which amyloid-beta (Aβ) peptide is generated. Aβ generation and aggregation as plaques are well known in the age related dementia, Alzheimer's disease (AD). It has been demonstrated that Aβ is common feature of the HIV infected brain as well. Further, reactive oxygen species (ROS) production is upregulated by HAART. Importantly, ROS promote β-secretase expression; a mechanism by which HAART may promote cognitive dysfunction, even in immune-competent HIV infected individuals.