# The evolutionary landscape of HIV broadly neutralizing antibody development

> **NIH NIH DP2** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $462,000

## Abstract

PROJECT SUMMARY
The human immunodeficiency virus (HIV) pandemic remains a global health threat, responsible for an
estimated 35 million active infections and one million deaths per year. Small molecule drugs have transformed
HIV prognosis and prophylaxis, but a preventative vaccine that elicits protective neutralizing antibodies is a
critical priority. Because of HIV’s vast global diversity, it remains an open challenge to elicit antibodies via
vaccination with sufficient antiviral breadth and potency to protect against diverse viral isolates. Rare broadly
neutralizing antibodies (bnAbs) that can inhibit the majority of circulating HIV strains have been isolated from
HIV-infected patients, establishing a targeted endpoint for an effective HIV vaccine. These bnAbs are also
promising molecules for direct therapeutic or prophylactic use. However, our understanding of HIV bnAb
function and development has not yet proven sufficient to effectively harness their protective potential. In this
proposal, I outline innovative high-throughput biochemical approaches to study the molecular evolutionary
basis for bnAb function. With a focus on bnAbs targeting the HIV Envelope CD4 receptor-binding site, we will
use high-throughput mutational scanning methods to reveal how all amino acid mutations in select bnAbs and
their naive precursors impact specificity versus breadth of binding to diverse HIV Env antigens and to rationally
designed candidate vaccine immunogens. In parallel, we will measure mutational effects on orthogonal
antibody properties that can constrain antibody development including thermodynamic stability, polyspecificity,
and autoreactivity. By synthesizing this wealth of mutational data together with existing natural antibody
sequencing data from infection and vaccination, we will identify the molecular evolutionary forces that guide
and constrain bnAb affinity maturation. These observations will enable the design of improved antibody
therapeutics and vaccine immunogens for this promising class of HIV bnAb. More broadly, the proposed
studies will provide important perspectives on the molecular and evolutionary basis for antibody development
and pioneer interdisciplinary methodological approaches with utility for various pathogens where the need for
broad immune recognition presents a challenge to therapeutic control.

## Key facts

- **NIH application ID:** 10913611
- **Project number:** 5DP2AI177890-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Tyler Nelson Starr
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $462,000
- **Award type:** 5
- **Project period:** 2023-08-24 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10913611

## Citation

> US National Institutes of Health, RePORTER application 10913611, The evolutionary landscape of HIV broadly neutralizing antibody development (5DP2AI177890-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10913611. Licensed CC0.

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