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

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. 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. 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. 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. © 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

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