Antigen presenting cells (APCs) detect pathogens in tissue and then shape T cell mediated adaptive immunity. They are comprised of multiple subsets of dendritic cells (DC), Langerhans cells (LC) and macrophages, which are now mostly well defined. However, the precise subsets present in specific human HIV transmission tissues can differ, and these differences are key to understanding viral pathogenesis and inform vaccine design. This is especially the case for anogenital tissues that contain a rich and complex microbiome, meaning that some degree of inflammation is always present, and must contain a different complement of APCs than steady-state tissue. Importantly, inflammation is now the established context in which HIV transmission occurs.

We have established access to every human anogenital tissue that HIV may encounter, freshly discarded from surgery, and foreskins obtained from Papua New Guinea in a range of defined inflammatory states.

Using scRNA-seq, flow cytometry and spatial proteomics we have defined the APCs and T cells that inhabit each of these tissues and defined those that bind HIV and then transmit the virus to T cells. We show that inflamed tissues contain a richer array of APCs and that DCs and T cells preferentially co-localise in response to HIV exposure. We also show that DCs migrate to the epithelial surface to capture HIV, though what mediates this migration remains unknown. In rectal tissue, we show that specific subsets of macrophages take up HIV and transfer HIV to T cells. This is significant as their role in HIV transmission has been poorly studied, and although they are very weak at stimulating de novo T cell responses, they have been shown to stimulate already primed T cells in mice. Expanding our knowledge of these early APC:HIV interactions will allow for supplements to current therapies and new targets for next generation vaccine design.