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Understanding the mechanisms of HIV tissue persistence necessitates the ability to visualize tissue microenvironments where infected cells reside; however, technological barriers limit our ability to dissect the cellular components of these HIV reservoirs. Here, we developed protein and nucleic acid in situ imaging (PANINI) to simultaneously quantify DNA, RNA, and protein levels within these tissue compartments. By coupling PANINI with multiplexed ion beam imaging (MIBI), we measured over 30 parameters simultaneously across archival lymphoid tissues from healthy or simian immunodeficiency virus (SIV)-infected nonhuman primates. PANINI enabled the spatial dissection of cellular phenotypes, functional markers, and viral events resulting from infection. SIV infection induced IL-10 expression in lymphoid B cells, which correlated with local macrophage M2 polarization. This highlights a potential viral mechanism for conditioning an immunosuppressive tissue environment for virion production. The spatial multimodal framework here can be extended to decipher tissue responses in other infectious diseases and tumor biology. [Display omitted] • Development of a method (PANINI) for multiplexed nucleic acid and protein imaging • Identification of orchestrated immune events in response to SIV infection • IL-10 levels in B cells and macrophages correlate with immunosuppression • Tissue microenvironmental cues can influence SIV viral transcription state Our understanding of persistent HIV tissue reservoirs is constrained by our limited ability to visualize the cellular components of these viral reservoirs. Jiang et al. develop a robust method that combines nucleic acid and protein imaging, termed PANINI, and use it to uncover the orchestrated immune events of retroviral lymphoid tissue reservoirs. [ABSTRACT FROM AUTHOR]