Identification of Protective Innate Immune Memory Responses Against HIV Acquisition in the Human Female Genital Tract

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PROJECT SUMMARY The main route for HIV acquisition in women of worldwide is sexual transmission. The low rate of HIV transmission per sexual act (0.08%) in women indicates that local innate immune mechanisms contribute to protection. Yet, the mucosal events that lead to the prevention or acquisition of HIV in the female genital tract (FGT) are largely unknown. Thus, it is critical to identify the early mucosal mechanisms that prevent HIV infection of target cells, in order to develop effective preventive approaches for women. Trained immunity is the functional modification of innate immune cells after initial stimulation that generates heightened innate immune responses to heterologous secondary stimulations. It can be induced by bacterial, fungal, and viral components through infection or vaccination, and leads to long-lasting epigenetic modifications in hematopoietic stem cell progenitors. This implies that trained innate cells can reach mucosal surfaces by replenishment of tissue-resident cells with new trained cells from the bone marrow or be generated after exposure to the microbiome and mucosal infections. However, the contribution of trained immunity to immune protection in human mucosal surfaces, including the FGT, is completely unknown. The PI’s research group recently discovered that dendritic cells and neutrophils in the FGT, innate cells involved in HIV pathogenesis, express transcripts and secrete cytokines and antimicrobials characteristic of trained immune responses and with known anti-HIV activity. Based on these preliminary results, the hypothesis being tested here is that genital DCs and neutrophils protect against HIV acquisition through trained innate immune responses. The proposed project builds on the PI’s prior work, and now seeks to define the trained immune signatures of genital DCs and neutrophils and determine how innate trained immunity contributes to anti-HIV mucosal protection of women. Single-cell sequencing approaches to define the phenotypical, transcriptional, and epigenetic signatures of trained DCs and neutrophils will be combined with in vitro functional assays to directly determine anti-HIV activity. It is expected that these studies will define, for the first time, how trained immune cells in the FGT contribute to protection against HIV acquisition. The identification of an inducible/modifiable form of innate protection against HIV in the FGT would represent a breakthrough in our understanding of how HIV acquisition occurs in the mucosa. Equally important, these findings will have a positive translational impact, since the identification of targetable cells and mechanisms of trained immunity responsible for anti-HIV protection will serve as the foundation to develop novel prevention strategies against HIV acquisition in women worldwide.