Multimodal PET-CT imaging of SIVmac239 dynamics post-ART interruption

PROJECT SUMMARY A major obstacle to HIV-1 eradication is the persistence of infected cells despite suppressive antiretroviral therapy (ART). HIV-1 predominantly resides in immune compartments that are difficult to access through routine sampling in people with HIV (PWH), limiting our understanding of the tissue burden of HIV-1 and the dynamics of viral reservoirs. This also hampers our ability to explore the relationship between active viral reservoirs and anatomical recrudescence following analytical treatment interruption (ATI), as well as the changes in reservoir dynamics during various stages of infection. Non-invasive techniques, such as positron emission tomography (PET) imaging, are urgently needed to directly assess HIV burden in vivo and evaluate potential HIV cure strategies. Our group has pioneered the first-in-human use of PET immunoimaging to target the HIV-1 envelope (Env) protein, enabling the identification of regions where HIV-1 protein persists and continues to exhibit translational activity in PWH, both on and off ART. Additionally, we have developed a second imaging approach using PET tracers targeting CD30, a non-viral biomarker associated with transcriptionally active HIV infection. Our findings show that HIV RNA is highly enriched in CD30+CD4+ T cells under suppressive ART, and in vivo targeting of CD30 with the cytotoxic antibody-drug conjugate (ADC) brentuximab-vedotin (BV) leads to a reduction in both HIV RNA and DNA. Importantly, CD30 expression strongly correlates with HIV RNA levels in lymphoid tissues, suggesting that CD30 may serve as a more sensitive marker for transcriptionally active HIV infection in the context of ART, particularly for PET imaging. The goal of this project is to use multimodal PET immunoimaging with zirconium-89 (89Zr)-labeled SIV Env or CD30 tracers to directly visualize sites of viral persistence and identify early tissue foci of viral rebound in SIVmac239-infected rhesus macaques (RM) undergoing ART. Additionally, we aim to explore whether near-simultaneous PET imaging of T cell activation (using [18F]F-AraG) alongside SIV Env or CD30 expression can help define the spatial relationships between virus persistence and adaptive immune responses. Finally, we will combine PET imaging of T cell activation with SIV Env or CD30 expression to track the dynamics of both viral and T cell responses following mRNA/SIVgag or control vector vaccination during ART and after ATI. To further validate these findings, PET imaging will be paired with targeted biopsies of deeper tissues, enabling a comprehensive evaluation of tracer specificity and immune activity. This approach will provide critical insights to support the clinical development and application of PET immunoimaging in PWH as a tool for HIV eradication therapeutic development.