Characterising Human Colorectal Mononuclear Phagocytes and Investigating their Role in Early HIV Infection

Abstract

In 2023, there was one HIV-related death every minute. Despite advances in antiretroviral therapy (ART), HIV remains a global pandemic with 40 million people infected and over one million new cases annually. ART can be used as pre-exposure prophylaxis (PrEP), but low uptake in high-risk groups and reduced effectiveness in inflamed tissues contribute to continued transmission. Without a cure or vaccine, enhancing current prevention strategies is vital. This requires a deeper understanding of early HIV transmission, particularly in high-risk tissues like the human colorectum, which remains under-researched.

Mononuclear phagocytes (MNPs), early responders to HIV, use pattern recognition receptors to bind the virus and facilitate its spread to CD4 T cells. In this thesis, optimised tissue digestion and high-parameter flow cytometry were used to categorise human colorectal MNPs into three macrophage subsets: monocyte-derived macrophages (MDM), transitional-MDM (t-MDM), and tissue-resident Macrophages, as well as three dendritic cell (DC) subsets: cDC1, CD207⁺ cDC2, and CD207⁻ cDC2. Each subset showed distinct expression profiles of HIV entry and lectin-binding receptors. Macrophages and t-MDMs were most effective at binding and internalising HIV within two hours. All MNPs enhanced HIV infection of CD4 T cells, but DCs and t-MDMs were more efficient in transferring the virus, whereas macrophages appeared to play a more significant role in establishing the tissue reservoir. A landmark high-parameter flow cytometry panel is also presented to compare MNPs across both steady-state and inflamed sexual transmission tissues and assess their capacity to take up HIV.

Understanding which MNP subsets contribute to HIV transmission in the colorectum is key to developing new, potentially mucosal-targeted PrEP strategies. These approaches could increase PrEP compliance, reduce transmission rates, and aid in the eradication of this of this global pandemic.