HIV eradication will become a tangible reality once virus spread is limited and reconstitution of the immune system is achieved. This U19 is focused on reaching that goal using cell-based therapies that include the transplantation of genetically-modified auto and allogeneic hematopoietic stem cells (HSCs), engineered to be resistant to infection HIV. This strategy is hypothesized to both limit the spread of HIV and reconstitute the immune system with new innate and adaptive cells that have not been exposed to the immunosuppressive effects of an ongoing HIV infection. To do this, the major objectives of this Core will be to identify host factors and mechanisms that influence the successful engraftment of gene-modified HIV-resistant HSCs, and impact their capacity to contribute to the decay of the HIV reservoir. To reach these objectives, the Core will implement a well-established and comprehensive transcriptional profiling approach to characterize defined subsets of effector and regulatory cells of both innate and adaptive immunity, in order to define mechanisms implicated in immune reconstitution, including the impact of inflammation on HSC transplantation. Systems biology approaches and computational biology in place have already allowed us to identify molecular pathways that affect HIV disease progression, size of the reservoir, and immune reconstitution. Specifically, the Core will provide centralized, SOP-driven services that include sample acquisition, genomic analysis, bioinformatic reporting, and the data management framework to acquire and manage data generated from Projects in the U19. A unique Illumina-based RNA-Seq transcriptomic platform will be used to identify and validate gene signatures that define pro- and anti- inflammatory cells and pathways that correlate with immune reconstitution and decay of the HIV reservoir in the setting of allo- and autologous BMT. The Core will also validate, by flow cytometry, gene expression profiles of pro- and anti-inflammatory cells and pathways that correlate with levels of immune reconstitution and decay of the HIV reservoir following allo- and autologous BMT. The Core will provide advanced bioinformatics analysis to investigators of the U19 and help with experimental design, analysis and modeling of transcriptional signatures. Finally, the Core will build an integrated database to mine for similar and different mechanisms of SHIV reservoir decay in allo- and autologous BMT, and to thereby benchmark and generate predictors of outcome for the NHP studies that will occur within the U19, and to compare them against features of immune responses that have resulted in decay of the HIV reservoir in other studies.
The work proposed in this Core will provide critical information that will guide the development of hematopoietic stem cell transplantation as a strategy for HIV eradication The work proposed in this Core will help to identify biomarkers that predict complete reconstitution of an immune system that can limit the spread of ongoing viral replication through effector mechanisms of innate and adaptive immunity.
