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Investigating Alterations of the Gut Microbiome and HIV-1 Pathogenesis Using Rhesus Macaque and Double Humanized-Mouse Models
The reciprocal relationship between gut microbiome and gut immune system is a critical determinant for human health and disease. The trillions of microbes that inhabit the gut may influence HIV-1 pathogenesis through interaction with the immune system. However, the cellular and molecular mechanisms of these interactions remain largely unknown. The overall objective of this dissertation was to determine the relationship between the gut microbiome and human immune system in the context of HIV-1 infection using animal models to provide new insights into HIV-1 pathogenesis. Using the Indian rhesus macaque-SIVmac251 model our results suggested that SIV infection can quickly lead to dysbiosis of the gut microbiota in both the rectum and jejunum. The major feature of gut microbial dysbiosis during SIV infection was the depletion of Clostridia taxa. We identified potentially pathogenic bacteria that correlated with viral infection status and viral load. Our data indicated that resolving gut inflammation and restoring homeostatic bacteria may be critical to mitigate the persistent immune activation observed during SIV/HIV infection. We also established a double humanized mouse model that harbors a functional human immune system and stable human-like gut microbiome. Importantly, transplanted human-like gut microbiomes were stable in mice for up to 14.5 weeks post-transplant. Microbiomes of double humanized mice also harbored predicted functional capacities that more closely resembled those of the human donors compared to humanized mice. Finally, we used the double humanized mice model to study the impact of HIV-1 infection and found changes in the human-like gut microbiome that corresponded with decreased human CD4+ T cell counts, systemic inflammation, and human immune cell activation. We then successfully created gut microbial dysbiosis using a high fat diet. Additionally, we found that dysbiosis was associated with markers of susceptibility to rectal HIV-1 transmission including increased systemic inflammation and immune activation. The double humanized mice model represents a unique and tractable new model to study the complex relationships between the human gut microbiome, human immune system and human disease in vivo. We believe that animal models will continue to be important for future studies of HIV-1.
Daharsh, Lance N, "Investigating Alterations of the Gut Microbiome and HIV-1 Pathogenesis Using Rhesus Macaque and Double Humanized-Mouse Models" (2020). ETD collection for University of Nebraska - Lincoln. AAI27955636.