This application is based on the serendipitous finding that URMC-099 can significantly boost antiviral activities of long acting antiretroviral therapy. Developed as a novel lead first-in-class mixed lineage kinase (MLK) inhibitor under development for use against HIV-1 associated neurocognitive disorders (HAND), URMC-099 was unexpectedly found to potentiate antiretroviral actions of nanoformulated ritonavir- boosted atazanavir (nanoATV/r). This drug combination led to a marked reduction of residual HIV-1 infection. URMC-099 facilitated nanoATV/r therapeutic effects by affecting the expression of the Rab family proteins that regulate endosomal vesicle trafficking, augmenting interactions between nanoATV/r and viral particles during the viral life cycle. Herein we will determine whether MLK inhibition from URMC-099 is involved in ATV/r's actions in the endosome, or if the findings are due to effects on other kinases targeted by this agent. Our recent demonstration that URMC-099 reduces neuroinflammation and is neuroprotective against HIV-1 proteins in vivo, and that the non-selective MLK inhibitor, CEP-1347 can increase ATV accumulation and half-life in HIV-1 infected patients bodes very well for this combination of chemotherapy to safely achieve viral eradication in the CNS while protecting neural homeostasis. We propose three specific aims to further delineate these interactions: (1) We will elucidate the pathways (mechanisms) responsible for URMC-099 facilitated nanoformulated antiretroviral responses in mononuclear phagocytes (MP;monocyte-derived macrophages [MDM] and microglia) in relation to MLKs and other related kinases targeted by URMC-099 (including kinases that mediate inflammation) and determine whether virus can be eradicated or merely suppressed. (2) To assess the impact of Rab family members identified in Aim 1 on potential drug toxicities from URMC-099 and nanoART in our models of HAND. To this end, we will investigate its roles in regulating MP and synaptic networks exposed to HIV-1 neurotoxins after URMC-099 and nanoART treatment. We will use in vivo models to further understand the role of Rabs as they relate to MLK activation and synaptodendritic damage with the idea of protecting the brain against further injuries. Finally, in (3) we will validate the utility of nanoformulated antiretrovral therapy (nanoART) and URMC-099 in clearance of persistently infected viral reservoirs in the CNS in our humanized CD34 engrafted model of neuroAIDS. Together, these aims will advance our approach to eradication of long-lived persistent infection of CNS MP while preserving synaptic architecture and function in disease.

Public Health Relevance

This application seeks to exploit a serendipitous finding that URMC-099, an enzyme inhibitor developed with support from the NIMH as add-on therapy for the brain disease associated with HIV-1 infection, can increase exposure of HIV-1 to a formulation of the protease inhibitor, atazanavir that allows it to gain increased access to a compartment where HIV-1 matures in infected white blood cells. This has the potential for great impact because it allows an infected white cell to get rid of the virus completely, eradicating a long-lived persistent reservoir of HIV-1 infection in the brain.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Colosi, Deborah
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University of Rochester
School of Medicine & Dentistry
United States
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Thomas, Midhun B; Gnanadhas, Divya Prakash; Dash, Prasanta K et al. (2018) Modulating cellular autophagy for controlled antiretroviral drug release. Nanomedicine (Lond) 13:2139-2154
Kiyota, Tomomi; Machhi, Jatin; Lu, Yaman et al. (2018) URMC-099 facilitates amyloid-? clearance in a murine model of Alzheimer's disease. J Neuroinflammation 15:137
McMillan, JoEllyn; Szlachetka, Adam; Slack, Lara et al. (2018) Pharmacokinetics of a Long-Acting Nanoformulated Dolutegravir Prodrug in Rhesus Macaques. Antimicrob Agents Chemother 62:
Zhou, Tian; Su, Hang; Dash, Prasanta et al. (2018) Creation of a nanoformulated cabotegravir prodrug with improved antiretroviral profiles. Biomaterials 151:53-65
Kevadiya, Bhavesh D; Ottemann, Brendan M; Thomas, Midhun Ben et al. (2018) Neurotheranostics as personalized medicines. Adv Drug Deliv Rev :
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Hammond, Jennetta W; Qiu, Wen Q; Marker, Daniel F et al. (2018) HIV Tat causes synapse loss in a mouse model of HIV-associated neurocognitive disorder that is independent of the classical complement cascade component C1q. Glia 66:2563-2574
AraĆ­nga, Mariluz; Edagwa, Benson; Mosley, R Lee et al. (2017) A mature macrophage is a principal HIV-1 cellular reservoir in humanized mice after treatment with long acting antiretroviral therapy. Retrovirology 14:17
Gnanadhas, Divya Prakash; Dash, Prasanta K; Sillman, Brady et al. (2017) Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs. J Clin Invest 127:857-873
Zhang, Gang; Guo, Dongwei; Dash, Prasanta K et al. (2016) The mixed lineage kinase-3 inhibitor URMC-099 improves therapeutic outcomes for long-acting antiretroviral therapy. Nanomedicine 12:109-22

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