Recently various HIV-1 infectable humanized mouse models (BLT, hNSG) have been advanced which show great promise for vaccine development. In this proposal, we will develop a new humanized mouse model for testing HIV-1 vaccines containing a-gal epitopes. Our previous work demonstrated that immunogenicity of HIV-1 gp120 protein engineered to express a-gal epitopes was 100-fold higher than that lacking the a-gal epitope in the a-1, 3-galactosyltransferase knockout (KO) mice which express anti-Gal antibodies. The enhancement is likely due to an increased uptake of vaccine antigen plus anti-Gal antibody complexes by antigen presenting cells. Unlike humans, the tissues in all existing humanized mouse models express a-gal epitopes, and lack B cells secreting anti-Gal antibodies. The new proposed humanized mouse model will be the first humanized non-primate animal model with tissues lacking a-gal epitopes and B cells secreting anti-Gal antibodies, as in humans. Specifically, we aim to: 1) construct the new mouse model by breeding the a1,3 GT knockout (KO) mice which lack a-gal epitopes and produce anti-Gal antibodies, with NSG mice (NOD/SCID IL2r gamma (null) and 2) the new mouse strain (referred as NSG/a-galnull) will be engrafted with human fetal tissues and CD34+ stem cells to develop a mature human immune system. 3) After engraftment, these new humanized mice will be used to test the efficacy of an HIV-1 gp140 trimer vaccine containing a-gal epitopes. We will assess induction of humoral and cellular immune responses to the vaccine as well protection from HIV-1 infection. Success of these studies will provide justification for testing a-gal expressing vaccines in monkeys which, like humans produce anti-gal antibodies and expedite pre-clinical development of HIV-1 vaccine candidates and human clinical trials.

Public Health Relevance

More than 40 million people are currently infected with HIV worldwide and a vaccine is urgently needed. We propose to generate a new mouse model that can be used to test novel HIV vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Research Grants (R03)
Project #
5R03AI089352-02
Application #
8204452
Study Section
HIV/AIDS Vaccines Study Section (VACC)
Program Officer
Bradac, James A
Project Start
2010-12-03
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2013-11-30
Support Year
2
Fiscal Year
2012
Total Cost
$77,188
Indirect Cost
$27,188
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215