# HIV-1 Env Immune Complexes and FcR-dependent Immunity

> **NIH NIH P01** · DUKE UNIVERSITY · 2020 · $587,915

## Abstract

ABSTRACT – Project 1
Rhesus macaque (RM) experiments and human clinical trials collectively indicate that broad protection against
HIV infection involves mechanisms of anti-envelope humoral immunity that reach beyond conventional
neutralizing activity. The most likely possibilities are Fc receptor (FcR)-dependent effector functions, including
antibody-dependent cell cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) or antibody-
dependent trogocytosis. Recent studies in murine models where Fc regions and Fc receptors (FcR) are
species-matched indicate that Fc-FcR interactions play an important role in antibody-mediated protection
against HIV even when Fab-mediated direct neutralizing activity is present. Nevertheless, whether RM and
humans exhibit similar relationships between protection and FcR-dependent immunity remains unclear. For
example, the RV144 clinical trial linked non-neutralizing anti-gp120 humoral immunity with decreased risk of
infection while passive immunization of RM with non-neutralizing human anti-envelope antibodies has failed to
block infection but instead decreased the number of transmitted viruses. Further, we found that RM antibodies
raised against an RV144-like vaccine regimen primarily mediate monocyte-directed trogocytosis against HIV
envelope; whereas immune sera from human vaccinees enables mainly NK-mediated killing. Such variances
must be reconciled before RM can be accurately used to model how HIV vaccine candidates and anti-envelope
antibodies will function in humans. Accordingly, the hypotheses for this Program are that: a) mechanisms of
protective humoral immunity diverge in RM versus humans largely because of differences in FcR-dependent
effector functions; b) the elucidation of these differences will facilitate optimization of the RM model for HIV
vaccine development. Towards this goal, this Project will test a novel hypothetical model to explain how anti-
HIV envelope antibodies variably activate FcR-dependent effector functions in vivo. The key features of the
model are that: a) the formation of an HIV envelope immune complex allosterically induces a distinct Fc
structure (Immune Complex Fc, ICFc); b) the ICFc structure is marked by altered FcR binding compared to
free immunoglobulin; c) ICFc structures diverge between human and RM systems such that their respective
FcR preferences differ. Thus, dominant effector mechanisms can differ between macaques and humans
despite similar epitope targeting. Following our published work and preliminary data, this hypothesis will be
explored by examining HIV epitopes that arise during early replication. These include broadly neutralizing
epitopes as well as CD4-induced, transition state epitopes known to be potent targets for FcR-dependent anti-
HIV activity against cell-bound virions. This hypothesis will be tested in two specific aims: Aim 1. Establish
that HIV-1 envelope-IgG immune complexes have distinct, species-specific FcR binding profiles. Aim
...

## Key facts

- **NIH application ID:** 9925743
- **Project number:** 5P01AI120756-05
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** GEORGIA Doris TOMARAS
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $587,915
- **Award type:** 5
- **Project period:** — → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9925743

## Citation

> US National Institutes of Health, RePORTER application 9925743, HIV-1 Env Immune Complexes and FcR-dependent Immunity (5P01AI120756-05). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/9925743. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*