Summary
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.