Despite the widespread use of anti-retroviral therapy in AIDS patients, the prevalence of HIV-Associated Neurocognitive Disorders (HAND), including Asymptomatic Neurocognitive Impairment (ANI), Mild Neurocognitive Disorder (MND), and HIV-Associated Dementia (HAD), remains significantly high. Even mild forms of neurocognitive impairment may impact quality of life and antiretroviral drug adherence in H1V+ individuals (McArthur, 2004). The reason CNS complications may develop or persist in treated individuals is not known, but failure to eliminate viral reservoirs and inadequate drug penetration to the CNS could play a role in allowing low level viral replication to persist. For these reasons the development of novel compounds to treat HIV encephalitis (HIVE) is an objective of significant biomedical importance. In this project, we embark on proof-of-concept studies in nonhuman primates to test novel anti-Vif candidate drugs in support of efforts to accelerate basic and translational discoveries toward the advancement of new drug therapeutics for HAND. HIV-1 Vif is a highly attractive yet unrealized therapeutic target for the intervention of HlV-1 replication. HIV-1 Vif is essential for primate lentivirus replication in vitro. We have identified a lead Vif antagonist (RN18) that exhibits exquisite antiviral specificity against Vif-dependent viral replication. We plan to evaluate the in vivo efficacy ofthe most promising RN18 analogs in proof-of principal studies in a simian model of neuroAIDS. Vif antagonists with the most desirable antiviral activities, validated mechanism of action (Projects 1 and 2), and acceptable toxicity and pharmacokinetic profiles in rodents will be examined for in vivo antiviral activity in a monkey model of SIV-induced encephalitis (SIVE). We anticipate in vivo analysis of 2-3 Vif antagonists/year in groups of 6 animals each.

Public Health Relevance

Recent indications are that over 50% of HIV infected patients develop HIV-associated neurological disorder (HAND) despite receiving highly active antiretroviral therapy (HAART). There is significant need to develop novel therapeutic agents to prevent or reduce the progression of HAND. In Project 3, we will test novel Vif inhibitors and assess their efficacy in the SlV-infected macaque model of NeitroAIDS

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Program Projects (P01)
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Special Emphasis Panel (ZMH1-ERB-M)
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University of Miami School of Medicine
Coral Gables
United States
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Stevenson, Mario (2017) HIV persistence in macrophages. Nat Med 23:538-539
Honeycutt, Jenna B; Wahl, Angela; Baker, Caroline et al. (2016) Macrophages sustain HIV replication in vivo independently of T cells. J Clin Invest 126:1353-66
Mohammed, Idrees; Kummetha, Indrasena Reddy; Singh, Gatikrushna et al. (2016) 1,2,3-Triazoles as Amide Bioisosteres: Discovery of a New Class of Potent HIV-1 Vif Antagonists. J Med Chem 59:7677-82
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Stevenson, Mario (2015) Role of myeloid cells in HIV-1-host interplay. J Neurovirol 21:242-8
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Yang, Chao-Shun; Rana, Tariq M (2013) Learning the molecular mechanisms of the reprogramming factors: let's start from microRNAs. Mol Biosyst 9:10-7
Shen, Yang; Altman, Michael D; Ali, Akbar et al. (2013) Testing the substrate-envelope hypothesis with designed pairs of compounds. ACS Chem Biol 8:2433-41

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