Despite decades of HIV-1 vaccine research, there are no examples of immunogens or candidate vaccines that consistently elicit potent broadly neutralizing antibodies (bNAbs). Most examples of bNAbs come from natural HIV-1 infection of humans, but even then, they develop only after several years of infection and in only a subset of individuals. Nonetheless, the finding that humans have the potential to make potent bNAbs has spurred intensive research to identify the target epitopes of these antibodies and their developmental pathways from unmutated germline B cell receptor (BCR) to mature bNAb. Recently, research has focused on the coevolutionary pathways of bNAbs and HIV-1 Env sequences that elicit them in hopes of inferring particular Env sequences that can be developed into immunogens that engage and stimulate germline and intermediate ancestor BCRs. This strategy has been championed by investigators pursuing both ?B cell lineage design? and ?reverse vaccinology? approaches to vaccine development. We propose that a major roadblock to rational HIV- 1 vaccine design is the lack of an animal model where the induction of bNAbs can be achieved in a consistent and reproducible manner such that the molecular events responsible for bNAb elicitation can be deciphered and used to guide iterative HIV-1 vaccine design. This HIVRAD application proposes a novel hypothesis and an integrated research plan ? supported by promising new discoveries in SHIV biology, virus-Ab coevolution, and B lineage vaccine design ? to overcome this critical roadblock. We hypothesize that: (i) primary HIV-1 Env glycoproteins, if presented in their native conformation as persistently replicating SHIVs to outbred, genetically diverse rhesus macaques (RMs), will lead to consistent patterns of virus-Ab coevolution that recapitulate those patterns observed in humans infected by HIV-1 strains bearing homologous Envs; (ii) SHIVs containing primary HIV-1 Envs that in humans elicited bNabs, will bind orthologous germline and intermediate ancestor BCRs in RMs, and lead to the development of autologous and heterologous tier 2 neutralizing antibodies; and (iii) by identifying RM germline and intermediate ancestor BCRs that evolve to achieve neutralization breadth, together with their cognate SHIV Env immunogens (?immunotypes?), we will have in hand for the first time a reproducible experimental system in which to iteratively design, test and guide the development of novel vaccine candidates based on both B lineage design and reverse vaccinology platforms. To test this hypothesis, we propose three highly inter-related research projects and three cores: Project 1 - Env Evolution and Neutralizing Antibody Elicitation in SHIV Infected Rhesus Macaques and in Humans Infected by HIV-1 Strains bearing Homologous Envs (Shaw); Project 2 - Population Dynamics of Neutralizing B-Cell Responses in SHIV- infected Macaques (Kelsoe); Project 3 - Immunogen Design of HIV Sequential Envelopes Derived from SHIV- infected Macaques (Haynes). These projects will be enabled by Core A - Administrative (Shaw); Core B - Viral and Antibody Gene Sequencing (Hahn); and Core C - Bioinformatics and Statistics (Korber).

Public Health Relevance

A major roadblock to rational HIV-1 vaccine design is the lack of an animal model where the induction of broadly neutralizing antibodies (bNAbs) can be achieved in a consistent and reproducible manner and the molecular events leading to bNAb elicitation deciphered. This HIVRAD application proposes a new strategy to overcome this roadblock by using novel SHIVs as immunogens and novel B cell analytics to elucidate Env-Ab coevolutionary pathways, leading to innovative new strategies in B lineage based vaccine design.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Miller, Nancy R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Wagh, Kshitij; Kreider, Edward F; Li, Yingying et al. (2018) Completeness of HIV-1 Envelope Glycan Shield at Transmission Determines Neutralization Breadth. Cell Rep 25:893-908.e7
Fera, Daniela; Lee, Matthew S; Wiehe, Kevin et al. (2018) HIV envelope V3 region mimic embodies key features of a broadly neutralizing antibody lineage epitope. Nat Commun 9:1111
Song, Hongshuo; Giorgi, Elena E; Ganusov, Vitaly V et al. (2018) Tracking HIV-1 recombination to resolve its contribution to HIV-1 evolution in natural infection. Nat Commun 9:1928
Richard, Jonathan; Prévost, Jérémie; Baxter, Amy E et al. (2018) Uninfected Bystander Cells Impact the Measurement of HIV-Specific Antibody-Dependent Cellular Cytotoxicity Responses. MBio 9:
LaBranche, Celia C; McGuire, Andrew T; Gray, Matthew D et al. (2018) HIV-1 envelope glycan modifications that permit neutralization by germline-reverted VRC01-class broadly neutralizing antibodies. PLoS Pathog 14:e1007431
Prévost, Jérémie; Richard, Jonathan; Ding, Shilei et al. (2018) Envelope glycoproteins sampling states 2/3 are susceptible to ADCC by sera from HIV-1-infected individuals. Virology 515:38-45
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
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
Silva, Murillo; Nguyen, Thao H; Philbrook, Phaethon et al. (2017) Targeted Elimination of Immunodominant B Cells Drives the Germinal Center Reaction toward Subdominant Epitopes. Cell Rep 21:3672-3680
Roberts, Emily R; Carnathan, Diane G; Li, Hui et al. (2016) Collapse of Cytolytic Potential in SIV-Specific CD8+ T Cells Following Acute SIV Infection in Rhesus Macaques. PLoS Pathog 12:e1006135