HIV-1 infection is involved in many pathogenic processes in the body. While immunodeficiency and opportunistic infections represent the end-point of the disease process, significant co-morbidity occurs with CNS involvement resulting in neurocognitive decline and loss of quality of life. These are difficult problems to study either in people living with HIV-1 or in model systems. However, advances in the development if iPSC lines and in their differentiation into specific cell types and even multi-cell lineage organoids provide new opportunities to study the effects of insults to the cell types found in the brain in the cell culture setting. There are ongoing, concurrent epidemics of HIV-1, opioids, and amyloid fibril disease that all provide insults to the brain. HIV-1 infection often includes the use of suppressive therapy with questions of CNS penetration and viral latency. In addition, HIV-1 leads to a heightened state of inflammation, another toxic insult to the brain. HIV-1 infection and/or opioid use occur in a background of natural aging which often includes the subclinical deposition of amyloid fibrils. In this application we will look at the intersection of these phenomena as they affect HIV-1 infection and latency and also impact normal cell function. We will focus individually on microglia, astrocytes, and neurons then use the information obtained from the individual cells to study their interactions in organoids. This application brings together a team with expertise in neuroHIV, transcription analysis, opioid and HIV-1 interactions, organoids, and fibril disease. This interdisciplinary approach will allow us to exploit the CNS organoid model to develop new information that can ultimately be validated in whole organism studies in the future.
The brain is an especially sensitive target for a variety of insults. New organoid culture technology allows for these insults to be studied separately and together to understand their impact on cell function for the different cell types in the brain. HIV-1, with its associated inflammation and treatment, opioids, and amyloid fibril disease are all interesting, especially in our aging population. Important aspects of their intersection on brain cell functions can now be studied.
