HIV latency, persistence, and cure; humanized mice; protein kinase c
Human immunodeficiency virus (HIV) has had a catastrophic impact on individuals and communities around the world. It is estimated that over 35 million people are currently infected with this virus and a similar number have died of HIV/AIDS related causes. While combination antiretroviral therapy (ART) is capable of preventing disease progression, many people living with HIV do not have access to these drugs. ART is also complicated by drug-associated side-effects, the development of viral resistance, and significant financial expense. Moreover, because current therapies do not cure HIV infection, infected individuals have to continually take ART for life to suppress outgrowth of virus. Developing a cure for HIV is therefore an important research priority. My research goals are to work towards a safe and effective HIV cure by better defining the reservoirs that persist during ART and developing methods to eliminate them.
My laboratory uses in vitro and in vivo experimental models to study HIV infection, pathogenesis, treatment, and cure approaches. This includes in vitro model systems to study HIV infection and persistence in T cells and macrophages, and in vivo humanized mouse models of HIV infection. We are particularly focused on developing new approaches to eliminate the latent reservoirs of HIV that allow the virus to persist through years of drug treatment.
My undergraduate Bsc (Hons) degree in Medical Microbiology and Ph.D. in Molecular Virology were both obtained at the University of Edinburgh in Scotland, UK. From there I moved to UCLA as a postdoctoral scholar and subsequently a junior faculty member in the UCLA Department of Medicine. During this time I developed a research program that utilizes a range of model systems (including humanized mice) to study HIV latency and advanced new HIV cure approaches. I established my research laboratory at UCI in 2020, with appointments in the Departments of Microbiology and Molecular Genetics and Medicine (Division of Infectious Diseases).
Kim JT, Zhang T-H, Carmona C, Lee B, Seet CS, Kostelny M, Shah N, Chen H, Farrell K, Soliman MSA, Dimapasoc M, Sinani M, Blanco KYR, Bojorquez D, Jiang H, Shi Y, Du Y, Komarova NL, Wodarz D, Wender PA, Marsden MD, Sun R, Zack JA. Latency reversal plus natural killer cells diminish HIV reservoir in vivo. Nature Communications. 2022;13(1):121.
Pham V, Marsden MD#. Can macrophages form a latent reservoir of HIV? Future Virology. 2021 (In Press).
Marsden MD, Zhang TH, Du Y, Dimapasoc M, Soliman MSA, Wu X, Kim JT, Shimizu A, Schrier A, Wender PA, Sun R, Zack JA. Tracking HIV Rebound following Latency Reversal Using Barcoded HIV. Cell Reports Medicine (Cell Press). 2020;1(9):100162. PMCID: PMC7762775.
Pache L, Marsden MD, Teriete P, Portillo AJ, Heimann D, Kim JT, Soliman MSA, Dimapasoc M, Carmona C, Celeridad M, Spivak SM, Planelles V, Cosford NDP, Zack JA, Chanda SK. Pharmacological Activation of Non-canonical NF-kB Signaling Activates Latent HIV-1 Reservoirs In Vivo. Cell Reports Medicine (Cell Press). 2020, 1:100037.
Marsden MD#. Benefits and limitations of humanized mouse models in HIV persistence research. Retrovirology. 2020, 17(1):7.
Hardman C, Ho S, Shimizu A, Luu-Nguyen Q, Sloane J, Soliman M, Marsden MD#, Zack JA#, Wender PA#. Design, Synthesis and Evaluation of PKC Modulators for Enhanced Cancer Immunotherapy. Nature Communications. 2020, 11(1):1879.
Sloane JL.*, Benner N*, Keenan K*, Zang X*, Soliman M, Wu X, Dimapasoc M, Marsden MD*#, Zack JA#, Wender PA#. Prodrugs of PKC Modulators Show Enhanced HIV Latency Reversal and an Expanded Therapeutic Window. Proc Natl Acad Sci U S A. 2020, 117(20):10688-10698.
*Equal contributing authors. #Corresponding authors
Llewellyn GN, Seclen E, Wietgrefe S, Liu S, Chateau M, Pei H, Perkey K, Marsden MD, Hinkley SJ, Paschon DE, Holmes MC, Zack J, Louie S, Haase A, Cannon P. Humanized mouse model of HIV-1 latency with enrichment of latent virus in PD-1+ and TIGIT+ CD4 T cells. Journal of Virology. 2019 1;93 (10), e02086-18
Marsden MD#, Wu X, Mottahedan S, Loy BA, Schrier AJ, DeChristopher BA, Shimizu A, Hardman CT, Ho S, Ramirez CM, Wender PA#, Zack JA. Characterization of designed, synthetically accessible bryostatin analog HIV latency reversing agents. Virology. 2018; 520:83-93.
# Corresponding authors
Marsden MD, Zack JA. Humanized Mouse Models for Human Immunodeficiency Virus Infection. Annual Reviews in Virology. 2017;4(1):393-412.
Marsden MD, Loy BA, Wu X, Ramirez CM, Schrier AJ, Murray D, Shimizu A, Ryckbosch SM, Near KE, Chun T-W, Wender PA, Zack JA. In vivo activation of latent HIV with a synthetic bryostatin analog effects both latent cell "kick" and “kill" in strategy for virus eradication. PLoS Pathogens. 2017;Sep 21;13(9):e1006575.
Shimizu S, Ringpis GE, Marsden MD, Cortado RV, Wilhalme HM, Elashoff D, Zack JA, Chen IS, An DS. RNAi-Mediated CCR5 Knockdown Provides HIV-1 Resistance to Memory T Cells in Humanized BLT Mice. Mol Ther Nucleic Acids. 2015;4:e227.
Marsden MD, Zack JA. Double Trouble: HIV Latency and CTL Escape. Cell Host and Microbe. 2015;17(2):141-2.
Sanchez DJ, Miranda D, Jr., Marsden MD, Dizon TM, Bontemps JR, Davila SJ, Del Mundo LE, Ha T, Senaati A, Zack JA, Cheng G. Disruption of Type I Interferon Induction by HIV Infection of T Cells. PLoS One. 2015;10(9):e0137951. PMCID: 4574156.
Marsden MD, Zack JA. Experimental Approaches for Eliminating Latent HIV. Forum on Immunopathological Diseases and Therapeutics. 2015;6(1-2):91-9.
Marsden MD, Zack JA. Studies of retroviral infection in humanized mice. Virology. 2015;479-480:297-309. PMCID: 4424058.
Marsden MD, Zack JA. Neutralizing the HIV reservoir. Cell. 2014;158(5):971-2. PMCID: 4182933.
*Buehler DC, *Marsden MD, Shen S, Toso DB, Wu X, Loo JA, Zhou ZH, Kickhoefer VA, Wender PA, Zack JA, Rome LH. Bioengineered vaults: self-assembling protein shell-lipophilic core nanoparticles for drug delivery. ACS Nano. 2014;8(8):7723-32. PMCID: 4148163.
*These authors contributed equally to the work.
Beans EJ, Fournogerakis D, Gauntlett C, Heumann LV, Kramer R, Marsden MD, Murray D, Chun TW, Zack JA, Wender PA. Highly potent, synthetically accessible prostratin analogs induce latent HIV expression in vitro and ex vivo. Proc Natl Acad Sci U S A. 2013;110(29):11698-703. PMCID: PMC3718093.
Marsden MD, Zack JA. HIV/AIDS eradication. Bioorg Med Chem Lett. 2013;23(14):4003-10. PMCID: 3714230.
Liu SY, Aliyari R, Chikere K, Li G, Marsden MD, Smith JK, Pernet O, Guo H, Nusbaum R, Zack JA, Freiberg AN, Su L, Lee B, Cheng G. Interferon-inducible cholesterol-25-hydroxylase broadly inhibits viral entry by production of 25-hydroxycholesterol. Immunity. 2013;38(1):92-105. PMCID: 3698975.
Marsden MD, Kovochich M, Suree N, Shimizu S, Mehta R, Cortado R, Bristol G, An DS, Zack JA. HIV latency in the humanized BLT mouse. Journal of Virology. 2012;86(1):339-47. PMCID: PMC3255908
Marsden MD, Krogstad PA, Zack JA. Virologic evidence supporting the use of raltegravir in HIV post-exposure prophylaxis regimens. Antiviral Therapy. 2012;17 (7): 135-9.
*DeChristopher BA, *Loy BA, *Marsden MD, *Schrier AJ, Zack JA, Wender PA. Designed, synthetically accessible bryostatin analogues potently induce activation of latent HIV reservoirs in vitro. Nature Chemistry. 2012;4(9):705-10. PMCID: 3428736.
*These authors contributed equally to the work.
Kovochich M, Marsden MD, Zack JA. Activation of latent HIV using drug-loaded nanoparticles. PLoS One. 2011;6(4):e18270. PMCID: 3071729.
Marsden MD, Avancena P, Kitchen CM, Hubbard T, Zack JA. Single Mutations in HIV Integrase Confer High-Level Resistance to Raltegravir in Primary Human Macrophages. Antimicrobial Agents and Chemotherapy. 2011;55(8):3696-702. PMCID: 3147632.
Marsden MD, Burke BP, Zack JA. HIV latency is influenced by regions of the viral genome outside of the long terminal repeats and regulatory genes. Virology. 2011;417(2):394-9. PMCID: 3163716.
Marsden MD, Zack JA. Establishment and maintenance of HIV latency: model systems and opportunities for intervention. Future Virology. 2010;5(1):97-109. PMCID: PMC3037592.
Marsden MD, Zack JA. Eradication of HIV: current challenges and new directions. The Journal of Antimicrobial Chemotherapy. 2009;63(1):7-10.
Subramanian A, Gao B, Marsden MD, Galic Z, Kitchen S, Kacena A, Cheng G, Zack J. Macrophage differentiation from embryoid bodies derived from human embryonic stem cells. Journal of Stem Cells. 2009; 4:29-45.
Marsden MD, Xu J, Hamer D, Zack JA. Activating stimuli enhance immunotoxin-mediated killing of HIV-infected macrophages. AIDS Research and Human Retroviruses. 2008;24(11):1399-404.
Galic Z, Kitchen SG, Subramanian A, Bristol G, Marsden MD, Balamurugan A, Kacena A, Yang O, Zack JA. Generation of T lineage cells from human embryonic stem cells in a feeder free system. Stem Cells. 2008; 27:100-107.
Marsden MD, Zack JA. Human immunodeficiency virus bearing a disrupted central DNA flap is pathogenic in vivo. Journal of Virology. 2007; 81:6146-50.
Burke B, Brown HJ, Marsden MD, Bristol G, Vatakis DN, Zack JA. Primary cell model for activation-inducible human immunodeficiency virus. Journal of Virology. 2007;81(14):7424-34.
McCrossan M, Marsden M, Carnie FW, Minnis S, Hansoti B, Anthony IC, Brettle RP, Bell JE, Simmonds P. An immune control model for viral replication in the CNS during presymptomatic HIV infection. Brain. 2006;129(Pt 2):503-16.
Morris A, Marsden M, Halcrow K, Hughes ES, Brettle RP, Bell JE, Simmonds P. Mosaic structure of the human immunodeficiency virus type 1 genome infecting lymphoid cells and the brain: evidence for frequent in vivo recombination events in the evolution of regional populations. Journal of Virology. 1999;73(10):8720-31.
NIH P01 AI131294 (Project 1 PI) 08/10/17-07/31/22
R21 AI124763 (PI) 02/10/16-01/31/19 (NCE)
R56 AI124743 (Co-I) 8/13/2021-7/31/2022
Cellular and Molecular Biosciences