A new Northwestern Medicine study has uncovered a surprising molecular link between HIV-1 and a protein fragment associated with Alzheimer’s disease, according to findings published in the Proceedings of the National Academy of Sciences.
The study reveals how the replication of the virus in brain cells is hindered by the body’s own neurodegenerative processes, said Mojgan Naghavi, PhD, professor of Microbiology-Immunology and senior author of the study.
The new findings suggest that HIV-1’s ability to assemble and release new virus particles in macrophages and microglia — immune cells that act as viral reservoirs in the brain — is actually disrupted by a fragment of the amyloid precursor protein (APP) known as C99. This fragment, which is also linked to the progression of Alzheimer’s disease, blocks HIV-1’s access to multivesicular bodies (MVBs), the compartments where the virus typically assembles.
“Macrophages and microglia act as reservoirs for HIV-1, including in the brain where infection is associated with neurocognitive disorders,” said Naghavi, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “In T-cells, the plasma membrane is the primary site of HIV-1 budding, but in ‘professional phagocytes’ such as macrophages and microglia, intracellular multivesicular bodies serve as primary sites for HIV-1 assembly and budding. Yet we continue to have a limited understanding of what factors regulate this mode of replication and their implications for both HIV-1 replication and pathogenesis.”
Previous work from the Naghavi laboratory discovered that C99 impairs HIV-1’s ability to access MVBs. In response, the virus promotes the breakdown of C99 — but this defense mechanism inadvertently increases the production of toxic amyloids, which are harmful to brain cells.
“In this study, we reveal that two key host sorting proteins, namely the ESCRT protein TSG101 and vacuolar protein sorting subunit VPS4A, play distinct roles in the processing of APP and the HIV-1 Gag polyprotein,” Naghavi said. “This creates a central line of competition for these factors, but which drive processes that are detrimental to either the host or virus.”
The study found that when TSG101 is depleted, HIV-1 replication is impaired — unless APP is also reduced, suggesting a direct competition for this cellular machinery, Naghavi said. Meanwhile, the subunit VPS4A influences both the production of viral particles and the fate of APP fragments, adding another layer of complexity.
“From the host perspective, TSG101-mediated processing through MVBs is unwanted, as it produces toxic amyloids, yet HIV-1 requires these factors for proper assembly and budding,” Naghavi said. “In driving sorting to secretory MVB pathways, infection increases amyloidogenic processing yet creates competition from the CTF, C99, for access to factors such as TSG101.”
The findings offer a new understanding of how viral replication and neurodegenerative processes intersect in the brain.
“Our findings provide new insights into how APP and Gag sorting pathways intersect and result in conflicting vesicular sorting needs that determine the balance of HIV-1 replication and neurotoxic amyloid production during infection of microglia,” Naghavi said.
The team is now expanding the research to explore how these mechanisms play out in neurons.
“We are currently trying to utilize stem cell-derived neuronal cultures to investigate the role of APP in regulating both infection and neurotoxicity in collaboration with the laboratory of Evangelos Kiskinis, PhD, associate professor in the Ken and Ruth Davee Department of Neurology’s Division of Neuromuscular Disease and of Neuroscience,” Naghavi said.
Reference: Gu F, Naghavi MH. Negative interplay between HIV-1 Gag and amyloid precursor protein centers around competition for VPS4A and TSG101. PNAS. 2025;122(34):e2503988122. doi: 10.1073/pnas.2503988122
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