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

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Program Projects (P01)
Project #
5P01MH100942-02
Application #
8723305
Study Section
Special Emphasis Panel (ZMH1-ERB-M)
Project Start
2014-08-01
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
$379,223
Indirect Cost
$13,375
Name
University of Miami School of Medicine
Department
Type
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Patil, Veena S; Zhou, Rui; Rana, Tariq M (2014) Gene regulation by non-coding RNAs. Crit Rev Biochem Mol Biol 49:16-32
Nalam, Madhavi N L; Ali, Akbar; Reddy, G S Kiran Kumar et al. (2013) Substrate envelope-designed potent HIV-1 protease inhibitors to avoid drug resistance. Chem Biol 20:1116-24
Silver, Nathaniel W; King, Bracken M; Nalam, Madhavi N L et al. (2013) Efficient Computation of Small-Molecule Configurational Binding Entropy and Free Energy Changes by Ensemble Enumeration. J Chem Theory Comput 9:5098-5115
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