Dual Roles of Amyloid Beta in CNS Neuropathogenesis of HIV: Investigating Neuroprotective and Neurotoxic Mechanisms in HAND Progression

PROJECT SUMMARY/ABSTRACT HIV-associated neurocognitive disorder (HAND) remains a significant challenge for individuals living with HIV, even in the era of long-term antiretroviral therapy (ART). Despite ART’s success in suppressing peripheral viral replication, viral reservoirs in the brain contribute to neuroinflammation and cognitive decline. Amyloid beta (Aβ), a peptide traditionally associated with Alzheimer’s disease, has been identified as an antiviral immune effector, capable of directly binding to viral glycoproteins and inhibiting the entry of pathogens such as HSV-1 and influenza into host cells. However, Aβ’s dual role—both neuroprotective and neurotoxic—has not been fully explored in the context of HIV infection in the brain. This project aims to investigate how Aβ influences HIV neuropathogenesis by modulating viral entry in the CNS and its effects on neuroinflammation. Specifically, we hypothesize that Aβ binds to HIV’s envelope glycoprotein (Env) to prevent viral entry into microglial cells, the primary target in the CNS, while also promoting neuroinflammation and neuronal damage through its aggregation into neurotoxic forms. To test this hypothesis, we will integrate both computational and experimental approaches. Computationally, we will use molecular docking and molecular dynamics (MD) simulations to model interactions between Aβ and HIV Env across its various states (closed and open) and in the presence of CD4 and co-receptors CCR5 or CXCR4. The simulations will also account for viral tropism (R5-, X4-, and dual-tropic strains) to understand how Aβ affects HIV's ability to infect cells based on co-receptor usage. Ultimately, these simulations will provide insights into whether Aβ stabilizes non-fusogenic conformations of Env or disrupts co-receptor engagement, thus impairing HIV infectivity. Experimentally, we will use iPSC-derived microglia to validate the computational findings, assessing the impact of Aβ on HIV infectivity, co-receptor engagement, and microglial activation through flow cytometry, qPCR, and immunofluorescence microscopy. These studies will shed light on Aβ’s dual role in HIV neuropathogenesis and identify key molecular mechanisms driving HAND progression. The outcomes of this research will provide critical insights into the mechanisms underlying the evolution of HAND and uncover novel strategies for understanding and modulating HIV-induced neuroinflammation. Ultimately, this work may contribute to improved therapeutic approaches for mitigating the neurological complications of HIV infection, particularly in the context of ART-induced viral suppression.