Durham Research Center, 8020
985880 University of Nebraska Medical Center
Omaha, NE 68198-5880
HIV-1, Humanized mice, nanoART, Adjunctive therapy, Pharmacodynamics, HIV-1 associated neurocognitive disorders (HAND), drug-drug interaction
UNMC Today | February 6, 2018
Chemically modified drug shows promise for HIV treatment, elimination
My major focus is to understand the drug-drug interactions and signaling pathways by which drugs work in the context of HIV therapeutics. Thirty years after the discovery that HIV is the causative agent of AIDS there is still the problem of drug adherence, drug dosing and appearance of drug resistant strains and unfruitful targeting of drugs to the latent reservoirs in the patients. The goal of the laboratory is to better design long-acting formulations of existing antiretroviral drugs and also to develop new formulations, which can improve patients’ health.
We are currently working on developing a testing pharmacodynamic (PD) platform for the development of antiretroviral and adjunctive therapies for peripheral HIV-1 and for its related associated neurocognitive disorders. Also part of the team in the development and subsequent testing of novel ligand decorated antiretroviral formulations developed by our medicinal and polymer chemistry program for drug to drug interactions, for systemic toxicities, for testing reductions in residual viral load, for interrelationships between tissue histology (including lymphocyte and monocyte distribution) and quantitative proviral DNA and RNA measurements by sensitive PCR tests and by immunohistochemical p24 staining, assess the interrelationships between antiretroviral responses and metabolic profiling.
Another major project involves, the development of new drug formulations [long-acting antiretroviral +URMC-099 (MLK3-inhibitor)], which can increase the storage of drug formulations in specific endolysosomal compartments for several weeks, which can subsequently target and remove new infections in the lymphoid and peripheral organs. The mechanism of action of the above drug formulation is underway.
2015 - Conference on Retroviruses and Opportunistic Infections Young Investigator Award poster titled " Chemical Facilitated endosomal storage of long-acting antiretroviral nanoparticles," February 23-26, Washington State Convention Center, Seattle, WA, USA.
- Generation and HIV-1 infection of Hu-PBL mice
- Flow cytometry on blood and tissues
- Immunohistochemistry (IHC)
- Immunofluorescence (IF) microscopy and quantification using Nuance
- Harvesting of mice organs and tissue RNA and DNA isolation
- Cell culture and infections of cells with HIV-1
- Reverse transcriptase (RT) assay
- HIV-1 Viral load measurements
- Western blots
- Conventional PCRs and Real time-RT PCR
Prasanta K. Dash, R Kaminski, R Bella, H Su, S Mathews, T M Ahooyi, C Chen, P Mancuso, R Sariyer, P Ferrante, M Donadoni, J A. Robinson, B Sillman, Z Lin, J R. Hilaire, M Banoub, M Elango, N Gautam, R. L Mosley, L Y. Poluektova, J McMillan, A N. Bade, S Gorantla, I K. Sariyer, T H. Burdo, W Young, S Amini, J Gordon, J M. Jacobson, B Edagwa, K Khalili & H E Gendelman. Sequential LASER ART and CRISPR Treatments Eliminate HIV-1 in a Subset of Infected Humanized Mice. Nat Comm. (2019) 10:2753, PMID: 31266936
- Su H, Cheng Y, Sravanam S, Mathews S, Gorantla S, Poluektova LY, Dash PK*, Gendelman HE*. Immune Activations and Viral Tissue Compartmentalization During Progressive HIV-1 Infection of Humanized Mice. Front Immunol. 2019 Feb 28; 10:340. (PMID:30873181) (* Shared Corresponding Author).
- Thomas MB, Gnanadhas DP, Dash PK, Machhi J, Lin Z, McMillan J, Edagwa B, Gelbard H, Gendelman HE, Gorantla S. Modulating cellular autophagy for controlled antiretroviral drug release. Nanomedicine (Lond). 2018. Sep;13(17):2139-2154. (PMID:30129397)
- Sillman B, Bade AN, Dash PK, Bhargavan B, Kocher T, Mathews S, Su H, Kanmogne GD, Poluektova LY, Gorantla S, McMillan J, Gautam N, Alnouti Y, Edagwa B, Gendelman HE. Creation of a long-acting nanoformulated dolutegravir. Nat Commun. 2018 Feb 6;9(1):443. (PMID:29402886)
- Zhou T, Su H, Dash P, Lin Z, Dyavar Shetty BL, Kocher T, Szlachetka A, Lamberty B, Fox HS, Poluektova L, Gorantla S, McMillan J, Gautam N, Mosley RL, Alnouti Y, Edagwa B, Gendelman HE. Creation of a nanoformulated cabotegravir prodrug with improved antiretroviral profiles. Biomaterials. 2018 Jan; 151: 53-65. (PMID:29059541)
- Kevadiya BD, Woldstad C, Ottemann BM, Dash P, Sajja BR, Lamberty B, Morsey B, Kocher T, Dutta R, Bade AN, Liu Y, Callen SE, Fox HS, Byrareddy SN, McMillan JM, Bronich TK, Edagwa BJ, Boska MD, Gendelman HE. Multimodal Theranostic Nanoformulations Permit Magnetic Resonance Bioimaging of Antiretroviral Drug Particle Tissue-Cell Biodistribution. Theranostics. 2018 Jan 1;8(1):256-276. (PMID:29290806)
- Gnanadhas DP, Dash PK, Sillman B, Bade AN, Lin Z, Palandri DL, Gautam N, Alnouti Y, Gelbard HA, McMillan J, Mosley RL, Edagwa B, Gendelman HE, Gorantla S. Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs. J Clin Invest. 2017 Mar 1;127(3):857-873. (PMID:28134625)
- Zhang G*, Guo D*, Dash PK*, Araínga M, Wiederin JL, Haverland NA, Knibbe-Hollinger J, Martinez-Skinner A, Ciborowski P, Goodfellow VS, Wysocki TA, Wysocki BJ, Poluektova LY, Liu XM, McMillan JM, Gorantla S, Gelbard HA, Gendelman HE. The mixed lineage kinase-3 inhibitor URMC-099 improves therapeutic outcomes for long-acting antiretroviral therapy. Nanomedicine. 2016 Jan;12(1):109-22. (PMID:26472049) (* Shared First Author). Appeared in the cover page.
- Bade AN, Gorantla S, Dash PK, Makarov E, Sajja BR, Poluektova LY, Luo J, Gendelman HE, Boska MD and Liu Y. Manganese-Enhanced magnetic resonance imaging reflects brain pathology during progressive HIV-1 infection of humanized mice. Mol Neurobiol. 2015 June 11.
- Puligujja P, Arainga M, Dash P, Palandri D, Lee Mosley R, Gorantla S, Poluektova L, McMillan J and Gendelman HE. Pharmacodynamics of folic acid-receptor targeted antiretroviral nanotherapy in HIV-1 infected humanized mice. Antiviral Res. 2015 May 27. pii: S0166-3542(15)00129-1.
- Boska MD*, Dash PK*, Knibbe J, Epstein AA, Akhter SP, Fields N, High R, Makarov E, Bonasera S, Gelbard HA, Poluektova LY, Gendelman HE and Gorantla S. Associations Between Brain Microstructures, Metabolites and Cognitive deficits during Chronic HIV-1 Infection of Humanized Mice. Mol. Neurodegeneration. 2014 Dec 18; 9 (1): 58. (*- Equal Contribution).
- Dash PK, Gendelman HE, Roy U, Balkundi S, Alnouti Y, Mosley RL, Gelbard HA, McMillan J, Gorantla S, Poluektova L. Long-acting NanoART Elicits Potent Antiretroviral and Neuroprotective Responses in HIV-1 Infected Humanized Mice. AIDS. 2012 Nov 13; 26(17): 2135-44.
- Epstein AA, Narayanasamy P, Dash PK, High R, Bathena SP, Gorantla S, Poluektova LY, Alnouti Y, Gendelman H, Boska MD. Combinatorial assessments of brain tissue metabolomics and histopathology in rodent models of human immunodeficiency virus infection. J Neuroimmune Pharmacol. 2013 Dec; 8 (5) 1224-38.
- Dash PK, Gorantla S, Gendelman HE, Knibbe J, Casale GP, Makarov E, Epstein AA, Gelbard HA, Boska MD, Poluektova LY. Loss of Neuronal Integrity during Progressive HIV-1 infection of Humanized Mice. J Neuroscience. 2011 Mar 2; 31 (9): 3148-57.
- Kadiu I, Narayanasamy P, Dash PK, Jhang W, Gendelman HE. Biochemical and Biologic characterization of Exosomes and Microvesicles as Facilitators of HIV-1 Infection in Macrophages. J Immunol. 2012 Jul 15; 189(2): 744-54.
- Eggert D, Dash PK, Gorantla S, Dou H, Schifitto G, Maggirwar SB, Dewhurst S, Poluektova L, Gelbard HA, Gendelman HE. (2010) Neuroprotective activities of CEP-1347 in models of NeuroAIDS. J Immunology. 2010 Jan 15; 184 (2): 746-56.
- Eggert D, Dash PK, Serradji N, Dong CZ, Clayette P, Heymans F, Dou H, Gorantla S, Gelbard HA, Poluektova L, Gendelman HE. (2009) Development of a platelet-activating factor antagonist for HIV-1 associated neurocognitive disorders. J Neuroimmunology. 2009 Aug 18; 213 (1-2): 47-59.
- Dash PK, Siddappa NB, Mangaiarkarasi A, Roshan PB, Aruna VM, Mahadevan A, Shankar SK, Satishchandra P, Prasad VR and Ranga U. Expanded coreceptor use of HIV-1 subtype-C molecular clones isolated from an Indian demented subject: implications for HIV-1 associated dementia. Retrovirology 2008 Mar7; 5:25.
- Puligujja P, Balkundi SS, Kendrick LM, Baldridge HM, Hilaire JR, Bade AN, Dash PK, Zhang G, Poluektova LY, Gorantla S, Liu XM, Ying T, Feng Y, Wang Y, Dimitrov DS, McMillan JM, Gendelman HE. Pharmacodynamics of Long-acting Folic acid-receptor Targeted Ritonavir-boosted Atazanavir Nanoformulations. Biomaterials. 2015 Feb; 41: 141-50.
- Roy U, McMillan J, Alnouti Y, Gautam N, Smith N, Balkundi S, Dash P, Gorantla S, Skinner AM, Meza J, Kanmogne G, Swindells S, Cohen SM, Mosley RL, Poluektova L and Gendelman H. Pharmacodynamic and antiretroviral activities of combination nanoformulated antiretrovirals in HIV-1-infected human PBL-reconstituted mice. J infect Dis. 2012 Nov; 206(10): 1577-88.
- Gadad SS, rajan RE, Senapati P, Chatterjee S, Shandilya J, Dash PK, Ranga U, Kundu TK. HIV-1 Infection Induces Acetylation of NPM1 that Facilitates Tat Localization and Enhances Viral Transactivation. J Mol Biol. 2011 Jul 29; 410 (5): 997-1007.
- Bethel-Brown C, Yao H, Callen S, Lee YH, Dash PK, Kumar A, Buch S. HIV-1 Tat-mediated induction of Platelet-Derived Growth factor in Astrocytes: Role of Early Growth Response Gene 1. J Immunology. 2011 Apr 1; 186 (7): 4119-29.
- Sreenath K, Pavithra L, Singh S, Sinha S, Dash P K, Siddappa NB, Ranga U, Mitra D. and Chattopadhyay S. (2010) Nuclear Matrix Protein SMAR1 Represses HIV-1 LTR Mediated Transcription through Chromatin Remodeling. Virology 2010 25; 400(1): 76-85.
- Siddappa NB, Dash PK, Mahadevan A, Desai A, Jayasuryan N, Satishchandra P, Ravi V, Shankar SK, Ranga U. Identification of unique B/C recombinant strains of HIV-1 in the southern state of Karnataka, India. AIDS 2005 Sep 2; 19 (13) 1426-9.
- Siddappa NB, Dash PK, Mahadevan A, Jayasuryan N, Hu F, Dice B, Keefe R, Satish KS, Satish B, Sreekanthan K, Chatterjee R, Venu K, Satishchandra P, Ravi V, Shankar SK, Shankarappa R, Ranga U. Identification of subtype C human immunodeficiency virus type 1 by subtype-specific PCR and its use in the characterization of viruses circulating in the southern parts of India. J Clin Microbiol 2004 Jun; 42 (6): 2742-51.