Emerging data indicate that an HIV vaccine could protect by inducing sufficient titers of broadly-neutralizing antibodies that mediate both direct viral neutralization as well as Fc-dependent effector functions against the diverse strains of HIV. Recent antibody discovery efforts have revealed a large number of new broadlyneutralizing monoclonal antibodies (bnMAbs) with extraordinary potency and breadth, raising the prospect that protective titers could be practically achieved if similar bnMAb specificities could be induced. vStructural studies of these new bnMAbs have revealed that they utilize structural and genetic features that appear to be unique to humans. We therefore propose to employ the humanized BLT mouse model to evaluate and optimize vaccines targeting new highly potent bnMAbs. BLT mice possess human humoral, cellular, and innate repertoires. We have demonstrated that the human immune system in these mice supports sustained HIV infection and generates human class-switched neutralizing antibodies in response. In this project, we propose to take a three-pronged approach to optimize vaccines targeting these new bnMAbs in the BLT mouse model, in Aim 1, we will develop a more complete understanding of the human antibody response to HIV infection generated in BLT mice, in order to utililize this model system most effectively for vaccine research, including for HIV vaccine challenge studies.
In Aim 2, we will develop a more complete understanding of the ability of bnMAbs to protect against HIV infection following passive transfer to BLT mice in vivo, comparing b12, for which protection has been documented in the established macaque SHIV challenge model, with the new more potent and broad bnMAbs targeted by our current vaccine design efforts. Using selectively mutated antibodies, we will also compare the relative protective contributions of the neutralizing activities of these antibodies to their Fc receptor-dependent effector functions.
In Aim 3, we will employ BLT mice to evaluate and optimize novel epitope-focused immunogens and immunization regimens designed to induce potent and broad bnMAbs like VRC01, targeting the CD4-binding site, and 10E8, targeting the membrane proximal external region.

Public Health Relevance

HIV is a major threat to global health and a vaccine is urgently needed. This project will evaluate HIV infection, protection against infection by passive administration of antibody, and vaccine-induced immune responses, in humanized mice with the ultimate goal of developing a protective HIV vaccine that induces broadly-neutralizing antibodies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI104715-03
Application #
8788496
Study Section
Special Emphasis Panel (ZAI1-RRS-A)
Project Start
Project End
2016-01-31
Budget Start
2015-02-01
Budget End
2016-01-31
Support Year
3
Fiscal Year
2015
Total Cost
$973,960
Indirect Cost
$277,197
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Tokatlian, Talar; Kulp, Daniel W; Mutafyan, Andrew A et al. (2018) Enhancing Humoral Responses Against HIV Envelope Trimers via Nanoparticle Delivery with Stabilized Synthetic Liposomes. Sci Rep 8:16527
Martins, Mauricio A; Tully, Damien C; Pedreño-Lopez, Núria et al. (2018) Mamu-B*17+ Rhesus Macaques Vaccinated with env, vif, and nef Manifest Early Control of SIVmac239 Replication. J Virol 92:
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
Tully, Damien C; Ogilvie, Colin B; Batorsky, Rebecca E et al. (2016) Differences in the Selection Bottleneck between Modes of Sexual Transmission Influence the Genetic Composition of the HIV-1 Founder Virus. PLoS Pathog 12:e1005619
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

Showing the most recent 10 out of 21 publications