- Viral Immunology, HIV-1, Humanized mice, Interferon-alpha
B.Sc. University of Toronto
Ph.D. University of Alberta
As a postdoctoral researcher at University of Oxford Dr. Lavender was a member of the Innate Discovery Team within the Center for HIV/AIDS Vaccine Immunology (CHAVI) international consortium. Working within the intramural program of the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH), Dr. Lavender went on to develop the TKO-BLT humanized mouse model for the discovery and evaluation of HIV-1 therapeutics and HIV-1 cure strategies.
Our lab uses a novel and long-lasting bone marrow, liver and thymus (BLT) humanized mouse model that is produced using the triple knock-out (TKO) C57BL/6 rag2-/-, common gamma chain-/-, CD47-/- mouse strain. This TKO-BLT mouse model has proven valuable for the study of the human immune response, pathogenesis and evaluation of therapeutics against HIV-1 and other viral diseases. TKO-BLT mice are highly reconstituted with human leukocytes and form secondary immune organs. The mice support sustained HIV-1 infection, mount HIV-1-specific immune responses, have a functional complement system and exhibit the hallmarks of a genuine human HIV-1 infection. Uniquely, these mice are resistant to graft versus host disease, which plagues other BLT models, and remain highly reconstituted and healthy for at least twice as long as other models. These qualities make TKO-BLT mice particularly amenable to the long-term investigations required to study pathogenesis in chronic infections and to trial therapeutic strategies over extended periods.
We are using TKO-BLT mice to investigate the role of different interferon-alpha subtypes in controlling disease or driving pathogenesis. Previous work showed that the multiple human subtypes of interferon-alpha have differential abilities to control HIV-1. Current work is focussed on understanding the different effects individual interferon-alpha subtypes have on immunity to HIV-1. How some subtypes may be beneficial and help control infection while others may mediate the interferon-alpha-associated pathogenesis that occurs during chronic infection. Understanding the differential roles of interferon-alpha subtypes during HIV-1 infection may identify strategies to block the pathogenic effects of some subtypes while harnessing the beneficial anti-viral and immunological effects of others. Additionally, there are ongoing collaborative studies using TKO-BLT mice to understand the human immune response to haemorrhagic fever viruses including Ebola and Lassa Fever and to mosquito borne arboviruses that cause paediatric encephalitis. Finally, humanized mouse models all suffer from a deficiency in the B cell compartment that restricts their usefulness for vaccine trials. I wish to develop projects within the lab to better understand this deficiency and to refine and advance the model to become useful for preclinical vaccine trials to HIV-1 and other pathogens.
Lavender KJ, Pang WW, Messer RJ, Duley AK, Race B, Phillips K, Chan CK, Peterson K, Dudek T, Allen TM, Weissman IL, and Hasenkrug KJ. Genetic Disruption of CD47 tolerizes C57BL/6 Rag-/-yc-/- for substantial levels of BLT-humanization that supports sustained HIV infection and functional immune responses with no evidence of GVHD. Blood 122(25):4013-20. 2013.*
Selected by The Faculty of 1000 as a paper of special interest.
*Commentary: William G. Kerr Blood 2013 122:4003-4004
Lavender KJ, Gibbert K, Peterson KE, Van Dis E, Francois S, Woods T, Messer RJ, Gawanbacht A, Müller JA, Münch J, Phillips K, Race B, Harper MS, Guo K, Lee EJ, Trilling M, Hengel H, Piehler J, Verheyen J, Wilson CC, Santiago ML, Hasenkrug KJ, and Dittmer U. Interferon Alpha Subtype-Specific Suppression of HIV-1 Infection In Vivo. J Virol 90(13):6001-13. 2016.
Lavender KJ, Pace C, Sutter K, Messer RJ, Pouncey DL, Cummins NW, Natesampillai S, Zheng J, Goldsmith J, Widera M, Van Dis ES, Phillips K, Race B, Dittmer U, Kukolj G and Hasenkrug KJ. An advanced BLT-humanized mouse model for extended HIV-1 cure studies. AIDS 32(1):1-10. 2017.
Lavender KJ, Williamson B, Saturday G, Martellaro C, Griffin A, Hasenkrug KJ, Feldmann H, and J Prescott. Pathogenicity of Ebola and Marburg viruses is associated with differential activation of the myeloid compartment in humanized TKO-BLT mice. JID E-pub ahead of print. 2018.