Tunneling nanotubes are a novel mechanism for the propagation of HIV infection and neurodegeneration

An estimated that at the end of 2022, 39 million people were living with the Human Immunodeficiency Virus (HIV). After early primary infection, HIV enters the central nervous system (CNS), where it remains for the lifespan of the infected individual, principally for the generation of viral reservoirs. Half of the people living with HIV showed cognitive decline, associated with cognitive impairment in the era of effective antiretroviral therapy.

The pathology of the HIV infection of the brain is characterized by enhanced leukocyte infiltration, microglial activation, inflammation, neuronal dysregulation and loss, and blood-brain barrier dysfunction . However, the mechanisms that mediate impairment are still not

fully defined. In this K01 we propose that tunneling nanotubes (TNTs) facilitate HIV toxicity and infection within the CNS.

I will examine a unique mechanism of viral reactivation mediated by TNTs. We and others have identified that HIV induces the formation of a novel cell-to-cell communication system called TNTs during infection and reactivation. TNT, like Virological Synapses {VS), plays a key role in HIV spread and immune/ART evasion. However, a major difference between VS and TNTs is that TNTs are generated from viral reservoirs to uninfected cells, reaching distances up to 500 µm.

TNTs-mediated infection does not require cellular migration into areas with viral reservoirs or soluble viruses because these long processes, TNTs, target infectivity. Our proposal will explore how HIV induces TNT, its function, and the consequences of TNT in viral amplification and reactivation, as well as they can provide an alternate route for HIV spread of toxicity and aggregated proteins associated with neurological disorders.

This novel and innovative application will provide a unique perspective on the viral spread and reactivation mechanisms. Our central hypothesis is that "Viral reservoirs use TNTs to spread infection and bystander neuronal/glial damage in the current ART era." The innovation of the proposed research is the integration of robust preliminary data. This K01 corresponds to a high-risk high-reward application because the presence of TNTs in HIV, its clinical relevance, and the in vivo consequences of TNT inhibition are unknown and present gaps in knowledge.

This award will provide Dr. Valdebenito-Silva with the training and research support needed to successfully develop her research and become a scientist in the neuroscience field, who has the recognition of their peers as an independent investigator leader in this area of research. Furthermore, Dr. Valdebenito's work on the study of TNTs offers the potential to expand her research not only in studying other infectious diseases, such as neurotropic viruses, but also into neurodegenerative diseases, and cancer.