Toward Understanding the Role of Adult Human Microglia in the Ongoing Persistence of HIV and its Associated Neuropsychiatric Comorbidities

项目总结

PROJECT SUMMARY Despite effective suppression of HIV replication, current treatments do not provide sterilizing immunity or eradicate anatomical reservoirs. Studies conducted in HIV animal models and infected humans demonstrate the strong likelihood that the brain's long-lived microglia (MG) play an essential role in reservoir formation/maintenance. Elevated inflammatory cytokines and infected immune cells with HIV DNA have been found in the CSF of HIV-infected people on antiretroviral therapy (ART), revealing the increased risks to brain health and homeostasis. However, a deep understanding of the molecular mechanisms at work in human MG- HIV host-pathogen interaction that foments reservoir formation and maintenance has been very difficult and until recently, near intractable to study. Three key limitations must be overcome to achieve progress. First, is the limited ability to procure large quantities of adult human MG for experimentation. Second, cultured human MG must be relatively long-lived in vitro in order to conduct antiretroviral treatment interruption and reactivation studies. Third, to advance translational goals, an in vivo model to test the full complement of human adult MG function is needed and to validate mechanistic findings obtained in vitro. Exciting progress by several groups has been made on these fronts. Mathews et al., reported on the successful engraftment and HIV infection of human MG derived from fetal cord blood progenitors into the brains of NOG-IL-34 transgenic mice. A recent study by Rai et al., comparing transcriptomes found ~78% conservation in a previously validated MG conserved gene signature between human blood monocyte-derived MG, iPSC-derived human MG and human tissue adult MG that was not shared with two MG cell lines suggesting a possible path forward. Collectively, these data show that a subset of blood myeloid progenitors found in both mouse and man, retain genetic plasticity and resiliency built into a biological system that is overall crucial for proper brain functioning. The goals of this exploratory proposal are to build upon advances in culturing adult human MG from blood myeloid progenitors to allow study of somatic genetics and improve the translational potential of neuroHIV in vitro and in vivo experimental models. The long-term goal is to decipher the contribution of microglia and inflammatory stimuli to the maintenance of the HIV CNS reservoir. The Specific Aims are to: 1) characterize the extent, breadth and fidelity of human blood myeloid progenitors from unrelated adult healthy donors to populate and serve as HIV reservoirs in the brain and 2) identify and study the hierarchy of proinflammatory gene network expression kinetics in HIV-infected adult human microglia and impact on HIV persistence during ART. The findings from the proposed studies will lay the groundwork for deeper investigation of MG function, proinflammatory signaling, and the potential development of novel strategies for identifying and understanding the mechanisms and impact on mental health of HIV- infected myeloid reservoirs in the brain.