Molecular Imaging of persistent HIV: CD30

项目概述：根除艾滋病毒的一个主要障碍是存在持续存在的受感染细胞

PROJECT SUMMARY: A major hurdle to HIV eradication is the presence of infected cells that persist despite suppressive antiretroviral therapy (ART). HIV largely resides outside of the peripheral circulation, and thus, numerous anatomical and lymphoid compartments that have the capacity to harbor HIV are inaccessible to routine sampling. As a result, there is a limited understanding of the tissue burden of HIV and the anatomical distribution of HIV transcriptional and translational activity. Novel, non-invasive, in vivo methods, such as positron emission tomography (PET)-based imaging approaches may provide a means to visualize the reservoir. A PET-based imaging approach using a radiolabeled SIV anti-gp120 monoclonal antibody (mAb) has been applied to assess active infection in macaques, but similar approaches in humans have not been reported. However, the implementation of HIV envelope protein specific mAbs is likely to be challenging due to low expression of HIV proteins in the setting of suppressive ART. An alternative approach is to develop and implement tracers for non-viral biomarkers of HIV infected cells. CD30 is a member of the TNF receptor superfamily that is upregulated on various tumor cells (e.g. Hodgkin lymphoma) but not expressed on a vast majority of healthy cells. We recently demonstrated that HIV RNA is highly enriched in CD30+CD4+ T cells on suppressive ART, and targeting CD30 using the FDA approved cytotoxic antibody-drug conjugate (ADC) brentuximab-vedotin (BV) in vivo and ex vivo leads to reduced HIV RNA and DNA levels in some individuals. Importantly, CD30 mRNA expression in tissues from antiretroviral treated participants is found exclusively in HIV RNA+ cells. Because of the lack of expression on uninfected cells, CD30 is an enticing non-viral marker of transcriptionally active HIV-infected cells that persist despite suppressive ART. Therefore, we propose to: (1) Synthesize 89Zr-DFO-BV, (2) Collect IND enabling in vitro and in vivo data including estimate whole-body dosimetry in mice using µPET/CT, (3) Develop an efficient immunoreactivity assay to support clinical translation, (4) Validate and document the current Good Manufacturing Practice (cGMP) production of 89Zr-DFO-BV and (5) Conduct first-in-human PET/MR imaging of CD30 using 89Zr-DFO-BV in viremic, subjects under ART and uninfected controls to determine pharmacokinetics, dosimetry, proof of concept and safety. We hypothesize that radiolabeled BV will have activity against CD30 and have favorable dosimetry and pharmacokinetics for human use. Ultimately, PET/MR imaging of CD30 expressing CD4+ T cells has the potential to provide tissue-wide anatomical distribution of HIV transcriptionally active cells on ART. Our group has an established pre- clinical and clinical PET-MR imaging infrastructure and have three human studies involving imaging HIV persistence currently in process. As a result, this pilot study is feasible and has the capacity to provide a rigorous foundation for non-invasive imaging methods to enhance HIV eradication and therapeutic efforts.