Core B, the Animal and Laboratory Core, will provide both the humanized mice, and the HIV viral stocks to infect them with, for all experiments proposed in this application. Core B will generate BLT (bone marrowliver- thymus) humanized mice, which provide one of the recently improved humanized mouse models of HIV infection. BLT mice can be infected with HIV by vaginal transmission, and are capable of producing functional anti-HIV human immune responses. BLT mice are generated by the surgical implantation of human fetal thymic and liver tissue under the renal capsules of immunodeficient mice, concurrently with the intravenous transfer of autologous human hematopoietic stem cells. This protocol allows the human T cells that mature in these mice to be educated by autologous human thymic tissue rather than by the xenogenic mouse thymus. This autologous thymic education appears to result in the much improved T cell function, and consequently much improved human B cell function, that we and others have observed in BLT mice. Core B has already well-established capacity to provide Program investigators with the numbers of wellreconstituted BLT mice that they propose to study in this HIVRAD application. Core B will also perform the vaccinations and/or infections of BLT mice with HIV, and the subsequent harvesting of blood and tissues from these vaccinated and/or HIV-infected mice. Core B personnel have extensive experience in performing HIV studies in BLT mice with collaborating investigators. A strong safety plan is in place to minimize the risk of exposure to Core B personnel performing HIV infections and analyses of HIV-infected BLT mice, and emergency procedures are in place in case any exposure does occur. Core B will also work to improve the BLT model of HIV infection, by developing a low-dose repeated mucosal challenge model. Repetitive challenges will enable the mice to be infected with HIV doses that better represent those encountered in human heterosexual exposure. Core B will also provide virological support to all Program investigators. Core B will generate and titer the stocks of HIV used to infect BLT mice, and measure plasma viral loads in HIV-infected mice by qRT-PCR, using well-established Core B protocols. Core B has in place the demonstrated capacity to provide the multiple Clade B, A and C HIV strains that the experiments of this HIVRAD application will require. Core B thus is well-positioned to support all of the animal and virological requirements of the investigations proposed in this HIVRAD program.
There remains a great need for an animal model that can support investigations of HIV itself, as opposed to other similar viruses. The humanized mice and HIV viral stocks generated by Core B will enable Program investigators to address important questions about the generation and function of anti-HIV immune responses, in an in vivo setting that allows for the study of HIV itself interacting with human immune cells.
|Tully, Damien C; Claiborne, Daniel T; Allen, Todd M (2017) Interferon-I: The Pièce de Résistance of HIV-1 Transmission? Trends Microbiol 25:332-334|
|Ranasinghe, Srinika; Lamothe, Pedro A; Soghoian, Damien Z et al. (2016) Antiviral CD8+ T Cells Restricted by Human Leukocyte Antigen Class II Exist during Natural HIV Infection and Exhibit Clonal Expansion. Immunity 45:917-930|
|Deruaz, Maud; Moldt, Brian; Le, Khoa M et al. (2016) Protection of Humanized Mice From Repeated Intravaginal HIV Challenge by Passive Immunization: A Model for Studying the Efficacy of Neutralizing Antibodies In Vivo. J Infect Dis 214:612-6|
|Garcia-Beltran, Wilfredo F; Hölzemer, Angelique; Martrus, Gloria et al. (2016) Open conformers of HLA-F are high-affinity ligands of the activating NK-cell receptor KIR3DS1. Nat Immunol 17:1067-74|
|Moyer, Tyson J; Zmolek, Andrew C; Irvine, Darrell J (2016) Beyond antigens and adjuvants: formulating future vaccines. J Clin Invest 126:799-808|
|Liu, Haipeng; Irvine, Darrell J (2015) Guiding principles in the design of molecular bioconjugates for vaccine applications. Bioconjug Chem 26:791-801|
|Altfeld, Marcus; Gale Jr, Michael (2015) Innate immunity against HIV-1 infection. Nat Immunol 16:554-62|
|Karpel, Marshall E; Boutwell, Christian L; Allen, Todd M (2015) BLT humanized mice as a small animal model of HIV infection. Curr Opin Virol 13:75-80|
|Hotaling, Nathan A; Tang, Li; Irvine, Darrell J et al. (2015) Biomaterial Strategies for Immunomodulation. Annu Rev Biomed Eng 17:317-49|
|Mandal, Pankaj K; Ferreira, Leonardo M R; Collins, Ryan et al. (2014) Efficient ablation of genes in human hematopoietic stem and effector cells using CRISPR/Cas9. Cell Stem Cell 15:643-52|
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