# Targeting the HIV reservoir using optimized anti-HIV antibodies

> **NIH NIH R01** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2021 · $410,750

## Abstract

Summary
The rapid mutation rate of HIV-1 results in many thousands of viral strains, thus thwarting current vaccine
efforts. Although HIV-1 infection can be controlled by anti-retroviral therapy (ART), the virus rebounds within
weeks of ART cessation because complete elimination of HIV-1 is prevented by latent viral reservoirs. Broadly
neutralizing antibodies (bNAbs) against the HIV-1 envelope spike (Env) that have been isolated from a subset
of HIV-1–infected donors are protective against HIV-1 infection and can lower the viral load after infection, and
it has been suggested that bNAbs could play a role in eliminating the viral reservoir. However, HIV-1 can
evade even the most potent bNAbs by mutation. Here we seek to engineer bNAbs to be resistant to viral
mutation so they could be used to eliminate viral reservoirs. Our strategy relies upon harnessing avidity effects
to prevent viral resistance to bNAbs at both an individual and population level. We hypothesize that HIV-1
hinders IgGs from using both antigen-binding Fabs to bind bivalently. This is accomplished by the small
number and low density of HIV-1 Env spikes, which prevent most IgGs from inter-spike crosslinking (bivalent
binding between spikes), and the architecture of the Env trimer, which impedes intra-spike crosslinking
(bivalent binding within a spike). We suggested that predominantly monovalent binding expands the range of
HIV-1 mutations permitting Ab evasion, whereas reagents capable of bivalent binding through intra-spike
crosslinking would be more potent across multiple strains of HIV-1. This hypothesis was supported by our
demonstration of up to 100-fold increases in geometric mean potency achieved with our first generation intra-
spike crosslinking reagents (homo- and hetero-diFabs joined by rigid DNA linkers). These results support the
hypothesis that HIV's low spike density contributes to vulnerability of HIV-1 bNAbs to spike mutations and
suggests that the ideal anti-HIV therapeutic for eliminating HIV reservoirs would utilize avidity to achieve intra-
spike crosslinking because this sort of therapeutic would reduce the concentration required for sterilizing
immunity and be resistant to Env mutations. Here we propose to design, produce, and evaluate second
generation intra-spike crosslinking reagents with two improvements: (i) they will contain an IgG Fc to mediate
effector functions and increase the serum half-life, and (ii) the DNA will be replaced by structured protein
linkers. We will also evaluate the effects of Fc substitutions designed to enhance Fc-mediated effector
functions through tighter binding to activating FcγR receptors and improve serum half-life through enhanced
binding to FcRn, including a novel computational design strategy to improve binding to FcRn under conditions
that promote increased IgG half-life. These more potent bNAbs could be used therapeutically at lower
concentrations and thus reduce cost and/or production time, increase the number of pat...

## Key facts

- **NIH application ID:** 10179304
- **Project number:** 5R01AI129784-05
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Pamela J Bjorkman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $410,750
- **Award type:** 5
- **Project period:** 2017-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10179304

## Citation

> US National Institutes of Health, RePORTER application 10179304, Targeting the HIV reservoir using optimized anti-HIV antibodies (5R01AI129784-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10179304. Licensed CC0.

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