This P01 Program Project Grant is focused on optimizing the induction of vaccine-elicited human B cell and T cell responses against HIV utilizing the recently developed BLT (bone marrow, liver, thymus) humanized mouse model. While the SlV-infected macaque model has proven invaluable to HIV vaccine development, differences between macaque and human host genetics (e.g. MHC, TCR, BCR), as well as sequence differences between SIV and HIV, results in entirely distinct virus-specific responses in humans and macaques to these pathogens. Similarly, the cost and duration of HIV vaccine studies in humans limits the ability to rapidly conduct iterative studies to improve upon promising findings. As such, our ability to study, optimize and translate specific mechanisms by which human immune humoral and cellular immune responses control HIV in humans, especially with respect to immune specificity, remains restricted, as does our ability to identify approaches to best induce these precise types of responses in humans. This proposal builds on the investigators'strong track records in understanding neutralizing antibody and CD8+ T cell responses against HIV, and in developing novel nanoparticle delivery approaches to induce high levels of mucosal homing responses. Moreover, it translates these efforts into a newly developed BLT (bone marrow, liver, thymus) humanized mouse model of HIV infection that robustly supports HIV infection, and recapitulates human cellular and humoral immune responses, specificities, and characteristics critical to accurately defining the correlates of immune control and approaches to elicit protective vaccine-induced immunity.

Public Health Relevance

Understanding the precise mechanisms of immune control of HIV will be critical to the development of an effective HIV vaccine capable of recapitulating these responses. The recent development of the humanized BLT mouse model provides the unique opportunity to explore the correlates of immune protection against HIV and rapidly test iterative vaccine design approaches to optimize human responses to HIV. Project 1: Optimizing CD8+ T Cell Vaccine Responses Against HIV Project Leader (PL): Allen, Todd M. DESCRIPTION (as provided by applicant): Project 1 seeks to apply a rational approach to the optimization of an effective CD8+ T cell response to HIV, capitalizing on viral fitness constraint to exploit the natural limits of HIV sequence evolution and CD8 immunodominance hierarchies and the plasticity of the immune response to block viral escape pathways. It also brings to bear recent advances in high throughput genomic sequencing to tackle the enormous sequence diversity of HIV, while applying novel and potent nanoparticle-based vaccine adjuvant systems. Most importantly, it serves to translate identified correlates of immune control of HIV into a nove humanized mouse model capable of recapitulating HIV infection as well as human HIV-specific immune responses. Thus, this work will enable for the first time the direct study of human (not rhesus monkey) immune responses against HIV (not SIV) in order to define the mechanisms of this protection and iteratively improve vaccine approaches to optimize these effects. Project 1 responds to five specific objectives of the HIVRAD Program: 1) Identifying correlates of vaccine-induced immune protection to HIV/AIDS;2) How vaccine design can better address the heterogeneity of HIV;3) Improved animal model systems (and challenge viruses) to address vaccine efficacy;4) Approaches to increase the immunogenicity of HIV antigens (e.g., novel adjuvants), and 5) Determining how immune cells can be mobilized to the portal of infection, and will address the following specific aims:
Aim 1 : Characterize the magnitude, kinetics, specificity and efficacy of HIV-specific CD8+ T cell responses in the humanized BLT mouse model to facilitate studies of HIV-specific vaccine immunity.
Aim 2 : Determine whether vaccination can overcome natural CD8+ T cell immunodominance hierarchies to avoid targeting of 'decoy'CD8 epitopes, and induce variant-specific CD8+ T cell responses.
Aim 3 : Determine whether the induction of strong, mucosal-homing CD8+ T cell responses by novel nanoparticle delivery systems can prevent the early systemic dissemination of HIV in BLT mice.

Public Health Relevance

The newly developed humanized mouse model provides the unique opportunity to explore the correlates of immune protection of HIV by cellular immune responses within a system capable of supporting HIV infection and mounting human HIV-specific type responses. This model will also enable us to rapidly test iterative vaccine design approaches to further optimize cellular immune responses to HIV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI104715-02
Application #
8616335
Study Section
Special Emphasis Panel (ZAI1-RRS-A (J1))
Program Officer
Pullen, Jeffrey K
Project Start
2013-02-07
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$2,218,723
Indirect Cost
$657,786
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Liu, Haipeng; Moynihan, Kelly D; Zheng, Yiran et al. (2014) Structure-based programming of lymph-node targeting in molecular vaccines. Nature 507:519-22
Körner, Christian; Granoff, Mitchell E; Amero, Molly A et al. (2014) Increased frequency and function of KIR2DL1-3? NK cells in primary HIV-1 infection are determined by HLA-C group haplotypes. Eur J Immunol 44:2938-48
Seung, Edward; Dudek, Timothy E; Allen, Todd M et al. (2013) PD-1 blockade in chronically HIV-1-infected humanized mice suppresses viral loads. PLoS One 8:e77780
Tager, Andrew M; Pensiero, Michael; Allen, Todd M (2013) Recent advances in humanized mice: accelerating the development of an HIV vaccine. J Infect Dis 208 Suppl 2:S121-4
Seung, Edward; Tager, Andrew M (2013) Humoral immunity in humanized mice: a work in progress. J Infect Dis 208 Suppl 2:S155-9
Lavender, Kerry J; Pang, Wendy W; Messer, Ronald J et al. (2013) BLT-humanized C57BL/6 Rag2-/-?c-/-CD47-/- mice are resistant to GVHD and develop B- and T-cell immunity to HIV infection. Blood 122:4013-20
Dudek, Timothy E; Allen, Todd M (2013) HIV-specific CD8ýýý T-cell immunity in humanized bone marrow-liver-thymus mice. J Infect Dis 208 Suppl 2:S150-4