# Broadening autologous Tier 2 anti-HIV neutralizing antibodies

> **NIH NIH F31** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $492

## Abstract

Project Summary.
Despite over 30 year of effort, an effective HIV-1 vaccine has yet to be developed. The envelope glycoprotein
(Env) is the sole target for antibody-mediated protection from HIV infection. Animal immunizations with soluble
Env trimers (SOSIPs) derived from Tier 2 viruses have induced autologous neutralizing antibodies, but failed to
induce antibodies with sufficient breadth capable of neutralizing heterologous strains of HIV [1]. Monoclonal
antibodies (mAbs) with the ability to neutralize a broad array of HIV strains (bnAbs) have been isolated from
patients infected with HIV and these antibodies are capable of protecting against repeated viral challenge
when administered by passive infusion to non-human primates (NHPs) [2, 3]. BnAbs generally arise after 2 to 3
years of infection and despite targeting a variety of epitopes on Env most share common characteristics such
as high rates of somatic hypermutation (SHM) and unusually long heavy chain complementary determining
region 3 (HCDR3) [4]. This project seeks to broaden autologous Tier 2 neutralizing antibodies by both
increasing the level of SHM and directing SHM towards specific neutralizing epitopes.
Aim 1. Broaden the specificity of vaccine elicited autologous neutralizing antibodies via iterative
structure-based design of immunogens. High-resolution cryoEM structures of Env in complex with vaccine
elicited antibodies will be used delineate autologous neutralizing epitopes. Structure guided redesign of
neutralizing epitopes will focus on incorporating consensus amino acids in an effort induce cross-reactive
antibodies.
Aim 2. Increase the level of SHM by prolonging the duration of germinal center reactions using
continuous antigen delivery. BnAbs develop in presence of persistent antigen that is constantly evolving.
Implantable slow-release pumps will be used to mimic conditions of natural bnAb development.
Aim 3. Improve trafficking of immunogens to follicular dendritic cell (FDCs). Env immunogens are poorly
trafficked to FDCs due to high levels of glycosylation and poor complement fixation. Monoclonal antibodies that
bind to the base of Env immunogens will be used to form in vivo immune complexes with the goal of fixing
complement and improving trafficking to FDCs.

## Key facts

- **NIH application ID:** 10152258
- **Project number:** 3F31AI131873-03S1
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Christopher Andrew Cottrell
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $492
- **Award type:** 3
- **Project period:** 2017-02-01 → 2020-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10152258

## Citation

> US National Institutes of Health, RePORTER application 10152258, Broadening autologous Tier 2 anti-HIV neutralizing antibodies (3F31AI131873-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10152258. Licensed CC0.

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