Whole-body PET imaging of simian immunodeficiency virus using gp120-targeting probes fails to reveal regions of specific uptake in rhesus macaques

Eur J Nucl Med Mol Imaging. 2025 Jun;52(7):2645-2657. doi: 10.1007/s00259-025-07110-8. Epub 2025 Jan 31.

Abstract

Purpose: Following the initial reports demonstrating the feasibility of immunoPET imaging of simian immunodeficiency virus (SIV) using gp120-targeting monoclonal antibodies in non-human primates, replication efforts of the imaging system in human immunodeficiency virus (HIV)-infected individuals have yielded conflicting results. Herein, we used two anti-gp120 antibodies, 7D3 and ITS103.01LS-F(ab')2, to interrogate the reproducibility of gp120-targeting probes for immunoPET imaging of SIV in rhesus macaques.

Methods: The binding affinity estimates of 89Zr radiolabeled 7D3 and ITS103.01LS-F(ab')2 to SIV gp120, and the in-vitro and ex-vivo binding specificities of [89Zr]Zr-7D3 and [89Zr]Zr-ITS103.01LS-F(ab')2 to SIV Env expressing cells, primary cells, and tissue sections from uninfected and SIV-infected macaques were obtained through competition assays. The biodistributions of [89Zr]Zr-7D3 and [89Zr]Zr-ITS103.01LS-F(ab')2 were performed with static PET scans up to 6 days post-injection in 20 rhesus macaques and the standardized uptake values in various tissues were compared between SIV-infected and uninfected controls.

Results: Despite the demonstrated nanomolar affinity of [89Zr]Zr-7D3 and [89Zr]Zr-ITS103.01LS-F(ab')2 to SIV gp120, and strong binding specificity to SIV gp120 cell lines, we observed no discernible differences in their binding in primary cells, tissue sections of secondary lymphoid organs, in-vivo probe uptake between SIV-infected and uninfected macaques, or ex-vivo validation necropsies. While the probes remained stable in-vivo, only [89Zr]Zr-ITS103.01LS-F(ab')2 in chronic plasma retained its binding specificity to SIV gp120, with [89Zr]Zr-7D3 experiencing a > 97% reduction in binding to gp120 due to competition from endogenous antibodies at the 7D3 binding site.

Conclusion: The overall absence of specific uptake suggests inadequate binding potential (ligand affinity x target molarity) for these probes to effectively image SIV or HIV in-vivo, warranting further investigation into the lack of reproducibility observed with earlier non-human primate SIV imaging and conflicting human studies.

Keywords: 7D3; Endogenous antibodies; ITS103; ImmunoPET; Reproducibility; Rhesus macaques.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Biological Transport
  • Macaca mulatta
  • Membrane Glycoproteins
  • Positron-Emission Tomography* / methods
  • Radioisotopes
  • Simian Immunodeficiency Virus* / metabolism
  • Tissue Distribution
  • Viral Envelope Proteins
  • Whole Body Imaging* / methods
  • Zirconium

Substances

  • Zirconium
  • gp120 protein, Simian immunodeficiency virus
  • Zirconium-89
  • Radioisotopes
  • Antibodies, Monoclonal
  • Membrane Glycoproteins
  • Viral Envelope Proteins