John ('Chip') Tilton is an Associate Professor in the Department of Nutrition at Case Western Reserve University (CWRU). He is also Director of Immunobiology of the CWRU Center for Proteomics and Bioinformatics and holds a secondary appointment in the Department of Molecular Biology and Microbiology. Chip received his BA in Molecular Biology from Princeton University in 1995 and an MD from Yale University in 2001. Before beginning his laboratory at CWRU, Chip was a clinical research fellow at the National Institutes of Health and a senior research investigator at the University of Pennsylvania.
Dr. Tilton’s work focuses on the factors that regulate the susceptibility of host cells to infection by HIV and determine the types of cells than can be infected by the virus. More recently, Dr. Tilton's laboratory has been pursuing strategies to co-opt the virus as a therapeutic platform to deliver proteins into the cytoplasm and nucleus of living cells in vitro and, eventually, in vivo. Non-infectious viral particles have been strategically engineered to render the particles safe and to maximize protein incorporation, giving rise to the nanoscale PrOtein Delivery (nanoPOD) platform. The laboratory is investigating the ability of nanoPODs loaded with therapeutic proteins to treat a variety of diseases from cancer to inborn errors of metabolism.
My lab repurposes viruses for in vivo delivery of protein and nucleic acid therapeutics. We understand the heterogeneity of viruses and other small particles using nanoscale flow cytometry and unravel unraveling mechanisms of extracellular vesicle-mediated fusion and intercellular signaling.
From the discovery of insulin nearly a century ago to the ongoing explosion of humanized monoclonal antibodies to treat a range of diseases, the field of protein therapeutics – treating diseases using proteins – has made significant contributions to the medical armamentarium. There are currently over 150 FDA-approved protein therapies, which is all the more remarkable when one considers that virtually all of these are limited to targets on the cell surface or outside of the cell with the exception of a handful of drugs used to treat lysosomal storage disorders. No protein therapeutics are active in the cytoplasm, nucleus, or other organelles inside of cells due to the lack of an efficient intracellular protein delivery system. To address these needs, we have developed a lentivirus-based nanoscale PrOtein Delivery (nanoPOD) platform that:
- Has been rationally engineered to improve safety and reduce toxicity.
- Is extremely efficient at delivering proteins to the cytoplasm of primary cells.
- Is compatible with a wide variety of proteins.
- Can be used for targeted intracellular protein delivery both in vitro and in vivo.
This platform leverages our ongoing research into cellular factors that regulate the susceptibility of cells to HIV infection and work from the broader HIV community to optimize protein delivery for therapeutic purposes.
- Lucera MB, Haqqani AA, Schlatzer DM, and Tilton JC. "Inhibition of histone acetyltransferases protects CD4+ T cells from HIV infection. In preparation."
- Lucera MB, Fleissner Z, Tabler CO, Schlatzer DM, Troyer Z, and Tilton JC. "A small molecule inhibitor screen for host factors regulating cellular susceptibility to HIV-1 reveals Rho family GTPases enhance post-entry viral events." In preparation.
- Tabler CA, Groft S, Schlatzer DM, Lucera MB, and Tilton JC. "Activation of latent HIV proviruses through lentiviral-mediated delivery of constitutively active IKKb protein." In preparation.
- Haqqani AA, Schlatzer DM, Li X, and Tilton JC. "A targeted mass spectrometry assay for detection of HIV Gag protein following induction of latent viral reservoirs." In preparation.
- Bonar M and Tilton JC. "Detection and sorting of HIV particles for downstream functional analysis by flow cytometry." In preparation.
- Tabler CA, Haqqani AA, Schlatzer DM, Li X, Koscumb P, Lundberg K, and Tilton JC. "Optimization of HIV for intracellular protein delivery: the nanoPOD platform." In preparation.
- Haqqani AA, Marek SL, Kumar J, Davenport M, Wang H, and Tilton JC. “Central memory CD4+ T cells are preferential targets of double infection by HIV-1”. Virol J. 12(1):184 (2015).
- Lucera MB, Tilton CA, Mao H, Dobrowolski C, Tabler CO, Haqqani AA, Karn J, Tilton JC. “The histone deacetylase inhibitor vorinostat (SAHA) increases the susceptibility of uninfected CD4+ T cells to HIV by increasing the kinetics and efficiency of postentry viral events.” J Virol. 88(18):10803-12 (2014).
- Tabler CO, Lucera MB, Haqqani AA, McDonald DJ, Migueles SA, Connors M, Tilton JC. “CD4+ Memory stem cells are infected by HIV-1 in a manner regulated in part by SAMHD1 expression.” J Virol. 88(9):4976-86 (2014).
- Tilton CA, Tabler CO, Lucera MB, Tilton JC. “A combination HIV reporter virus system form measuring post-entry event efficiency and viral outcome in primary CD4+ T cell subsets” J Virol Methods. Jan; 195: 164-169 (2014).
- Haqqani AA, Tilton JC. “Entry inhibitors and their use in the treatment of HIV-1 infection.” Antiviral Res. 98:158-170 (2013).
- Lobritz MA, Ratcliff AN, Marozsan AJ, Dudley DM, Tilton JC, Arts EJ. “Multifaceted mechanisms of HIV inhibition and resistance to CCR5 inhibitors PSC-RANTES and Maraviroc.” Antimicrob Agents Chemother. 57:2640-2650 (2013).
- Parrish, N, Wilen C, Banks L, Iyer S, Pfaff J, Salazar-Gonzalez J, Salazar M, Decker J, Parrish E, Berg A, Hopper J, Hora B, Kumar A, Mahlokozera T, Yuan S, Coleman C, Vermeulen M, Ding H, Ochsenbauer C, Tilton J, Permar S, Kappes J, Betts M, Busch M, Gao F, Montefiori D, Haynes B, Shaw G, Hahn B, Doms R. “Transmitted/Founder and Chronic Subtype C HIV-1 use CD4 and CCR5 receptors with equal efficiency and are not inhibited by blocking the integrin α4β7.” PLoS Pathog. May 8(5): e1002686. (2012).
- Wilen CB, Tilton JC, Doms RW. “HIV: cell binding and entry.” Cold Spring Harbor Perspectives in Medicine. 2(8). pii: a006866 (2012).
- Wilen CB, Tilton JC, Doms RW. “Molecular mechanisms of HIV Entry.” Adv Exp Med Biol 2012:223-242 (2012).
- Jiang C, Parrish NF, Wilen CB, Li H, Chen Y, Pavlicek JW, Berg A, Lu X, Song H, Tilton JC, Pfaff JM, Henning EA, Decker JM, Moody MA, Drinker MS, Schutte R, Freel S, Tomaras GD, Nedellec R, Mosier DE, Haynes BF, Shaw GM, Hahn BH, Doms RW, Gao F. “Primary infection by a human immunodeficiency virus with atypical coreceptor tropism.” J Virol. 85: 10669-10681 (2011).
- Wilen CB, Parrish NF, Pfaff JM, Decker JM, Henning EA, Haim H, Petersen JE, Wojcechowskyj JA, Sodroski J, Haynes BF, Montefiori DC, Tilton JC, Shaw GM, Hahn BH, Doms RW. “Phenotypic and immunologic comparison of clade B transmitted/founder and chronic HIV-1 envelope glycoproteins.” J Virol. 85:8514-27 (2011).