The human immunodeficiency virus type 1 (HIV-1) pandemic continues to spread in the absence of a preventative vaccine. Broadly neutralizing antibodies (bnAbs) against HIV-1 can prevent infection of nonhuman primates, but have thus far not been elicited by vaccination. The HIV-1 envelope is covered by a dense array of host glycans that, if recognized by vaccine-induced antibodies, could generate bnAbs. BnAbs with these specificities arise in natural infection. However, to date, vaccine strategies for eliciting anti-Env glycan antibodies have shown glycan-dependent epitopes to be poorly immunogenic. In my studies of rhesus macaques vaccinated with a group M consensus envelope, CON-S, that contains a substantial proportion of high mannose sugars, I have identified macaque plasma antibodies that block the binding of anti-glycan bnAbs to HIV-1 Env. CON-S Env gp140-immunized macaques also possess sufficient antibody titers for detection of direct glycan binding in their plasma, and I have been successful in isolating glycan-reactive rhesus monoclonal antibodies from CON-S Env-vaccinated animals. The central hypothesis of this application is that immunization with a recombinant Env that is heavily glycosylated with high mannose glycans--similar to the glycoforms present on HIV-1 virions--can induce glycan-dependent neutralizing antibodies, a subset of which are in bnAb lineages. The objectives of this application are to define the development and anti-HIV-1 functions of these novel Env-induced plasma anti-Env glycan antibodies. Thus, in Aim 1, existing and new recombinant blood memory B cell antibodies directed to glycan-dependent HIV-1 envelope epitopes will be produced and their anti-HIV-1 activity characterized.
In Aim 2, we will profile the ontogeny of vaccine-induced anti-glycan antibodies both with recombinant mAb production, computational inference of lineage members, and next-generation VHDJH sequencing. Finally, in Aim 3, we will interrogate the vaccine-induced HIV-1 Env glycan antibody repertoire in secondary lymphoid organs and mucosal tissue after immunization with antigenic, stabilized CON-S gp140 trimers. The results from these studies will be a major step forward in our effort to understand the immunogenicity of HIV-1 envelope glycans that comprise bnAb epitopes. The antibodies characterized here will provide templates for B cell lineage design of immunogens that enhance the glycan-dependent antibody lineages induced by Env vaccination in rhesus macaques and humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI120801-03
Application #
9277352
Study Section
HIV/AIDS Vaccines Study Study Section (VACC)
Program Officer
Miller, Nancy R
Project Start
2015-06-15
Project End
2020-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
3
Fiscal Year
2017
Total Cost
$759,765
Indirect Cost
$277,791
Name
Duke University
Department
Surgery
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Saunders, Kevin O; Santra, Sampa; Parks, Robert et al. (2018) Immunogenicity of NYVAC Prime-Protein Boost Human Immunodeficiency Virus Type 1 Envelope Vaccination and Simian-Human Immunodeficiency Virus Challenge of Nonhuman Primates. J Virol 92:
Alam, S Munir; Aussedat, Baptiste; Vohra, Yusuf et al. (2017) Mimicry of an HIV broadly neutralizing antibody epitope with a synthetic glycopeptide. Sci Transl Med 9:
Williams, Wilton B; Zhang, Jinsong; Jiang, Chuancang et al. (2017) Initiation of HIV neutralizing B cell lineages with sequential envelope immunizations. Nat Commun 8:1732
Bonsignori, Mattia; Kreider, Edward F; Fera, Daniela et al. (2017) Staged induction of HIV-1 glycan-dependent broadly neutralizing antibodies. Sci Transl Med 9:
Saunders, Kevin O; Nicely, Nathan I; Wiehe, Kevin et al. (2017) Vaccine Elicitation of High Mannose-Dependent Neutralizing Antibodies against the V3-Glycan Broadly Neutralizing Epitope in Nonhuman Primates. Cell Rep 18:2175-2188
Saunders, Kevin O; Verkoczy, Laurent K; Jiang, Chuancang et al. (2017) Vaccine Induction of Heterologous Tier 2 HIV-1 Neutralizing Antibodies in Animal Models. Cell Rep 21:3681-3690