This application proposes to use our model of HIV infection, synaptodendritic damage, and cognitive impairment in mice to address the objectives of RFA-MH-14-170 on establishment and persistence of HIV CNS reservoirs during ART and testing new strategies for mitigation of neurocognitive disease. We focus on mild HAND, neurocognitive impairment (NCI) less severe than dementia, termed HIV-NCI. We have shown that infection of conventional mice with a mouse-tropic chimeric HIV, EcoHIV, reproduces human HIV-NCI in chronic systemic infection, induction of immunity to control HIV in the periphery, early HIV neuroinvasion, and manifestation of a HIV-NCI-like symptomatic disease assessed in behavioral tests. The overall hypothesis of this project is that the biology of persistent HIV infection in CNS in the setting of suppressive ART and restored immunity differs fundamentally from that in peripheral tissues, thereby permitting continuing brain disease and necessitating novel strategies for disease control. We propose that HIV persists in CNS in a biologically active form in long-lived cells;that virus expression and secretion of neuropathogenic products persist despite antiviral drugs and anti-HIV immune responses. The hypothesis will be tested in EcoHIV infected mice using cognitive impairment in behavioral tests to assess the physiological relevance of our studies. Antiretroviral treatment, including CNS delivery, will be optimized using nanoART technology in collaboration with Dr. H. E. Gendelman.
The Specific Aims are: 1) Determine the time frame and mechanisms of establishment of HIV CNS reservoirs relative to induction of NCI and post-exposure ART. Using EcoHIV or EcoHIV-GFP, wildtype or CCL2-KO mice, staggered application of nanoART or CCL2 inhibitor, we will test the dynamics of brain infection and viral genome forms, cell types infected, synaptodendritic damage, and NCI induction related to antiviral immunity, ART timing, brain entry by HIV and by monocytes. 2) Determine the mechanisms of HIV persistence in CNS and NCI progression during chronic infection of mice with functional immunity, suppressed peripheral HIV, and chronic ART. In chronic infection with continuous, interrupted, or peripheral-only ART, test the extent of NCI compared to monocyte CNS entry, intra-CNS virus spread, HIV Tat activity in the brain, LPS- induced surges in virus expression, CD8 T cell infiltration, and synaptodendritic injury at the molecular level. 3) Test proof-of-principle of adjunct strategies for HIV provirus activation and silencing for their effects on HIV brain reservoirs and chronic HIV-NCI in the presence of ART. Provirus will be activated with HDAC inhibitors in use. Provirus silencing will include Type I IFN and Tat immunization. The effects of treatment on HIV expression will be correlated with improvement in synaptodendritic injury and HIV-NCI. Methods currently in use include two complementary behavioral tests, QPCR detection of integrated EcoHIV DNA in mouse tissues, gene expression and pathway analysis, dual staining fluorescence microscopy, and HIV immunization.
Although anti-retroviral treatment largely eliminates active HIV in the body, virus remains within the brain where it is less susceptible to existing treatments and it can continue to cause problems in memory and learning. Here we employ HIV infection of mice with various treatment strategies targeted to the brain to determine how we can interfere with the sanctuary of virus in the brain and prevent or treat brain disease.
|Olson, Katherine E; Bade, Aditya N; Namminga, Krista L et al. (2018) Persistent EcoHIV infection induces nigral degeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-intoxicated mice. J Neurovirol 24:398-410|
|Nedelcovych, Michael T; Gadiano, Alexandra J; Wu, Ying et al. (2018) Pharmacokinetics of Intranasal versus Subcutaneous Insulin in the Mouse. ACS Chem Neurosci 9:809-816|
|Nitkiewicz, Jadwiga; Borjabad, Alejandra; Morgello, Susan et al. (2017) HIV induces expression of complement component C3 in astrocytes by NF-?B-dependent activation of interleukin-6 synthesis. J Neuroinflammation 14:23|
|Nedelcovych, Michael T; Tenora, Lukáš; Kim, Boe-Hyun et al. (2017) N-(Pivaloyloxy)alkoxy-carbonyl Prodrugs of the Glutamine Antagonist 6-Diazo-5-oxo-l-norleucine (DON) as a Potential Treatment for HIV Associated Neurocognitive Disorders. J Med Chem 60:7186-7198|
|Geraghty, Patrick; Hadas, Eran; Kim, Boe-Hyun et al. (2017) HIV infection model of chronic obstructive pulmonary disease in mice. Am J Physiol Lung Cell Mol Physiol 312:L500-L509|
|Saylor, Deanna; Dickens, Alex M; Sacktor, Ned et al. (2016) HIV-associated neurocognitive disorder--pathogenesis and prospects for treatment. Nat Rev Neurol 12:234-48|
|Moidunny, Shamsudheen; Matos, Marco; Wesseling, Evelyn et al. (2016) Oncostatin M promotes excitotoxicity by inhibiting glutamate uptake in astrocytes: implications in HIV-associated neurotoxicity. J Neuroinflammation 13:144|
|Rappaport, Jay; Volsky, David J (2015) Role of the macrophage in HIV-associated neurocognitive disorders and other comorbidities in patients on effective antiretroviral treatment. J Neurovirol 21:235-41|
|Potash, Mary Jane; Hadas, Eran; Volsky, David J (2014) Response to 'Remarks on the article of Hadas et al.: Transmission of chimeric HIV by mating in conventional mice: prevention by pre-exposure antiretroviral therapy and reduced susceptibility during estrus'. Dis Model Mech 7:178-9|
|He, Hongxia; Sharer, Leroy R; Chao, Wei et al. (2014) Enhanced human immunodeficiency virus Type 1 expression and neuropathogenesis in knockout mice lacking Type I interferon responses. J Neuropathol Exp Neurol 73:59-71|
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