The role of TNTs in HIV and neurological diseases: a unique approach to prevent and cure these diseases
HIV is a major infectious disease worldwide, but in developed countries, HIV is becoming a chronic disease thanks to anti-retroviral therapy (ART); however, still several questions about the pathogenesis of the virus. A key unresolved question is how does HIV spread efficiently during acute infection and reactivation in the absence of a significant soluble virus? and despite multiple disadvantages, including physical and immune barriers, infection of poorly entry/replicating cells (DC and macrophages in the mucosa), few numbers of HIV-infected cells, the most produced virus is defective, upon infection/replication cells undergo apoptosis, immune neutralization, and ART for name some. HIV infection or reactivation is fast, reproducible, and successful despite all these issues, suggesting an efficient amplification mechanism. But these mechanisms are poorly understood. A key mechanism that avoids several of the mechanisms described above was discovering HIV transfer by the virological synapses (VS). VS is efficient even in the absence of a soluble virus but requires close cell-to-cell interactions between HIV-infected and uninfected cells, adding a level of complexity because HIV compromises migration as well. To address several of these issues, we recently identified a novel mechanism of long-range cell-to-cell mediated infection by Tunneling Nanotubes (TNTs) that avoid most of the disadvantages described above. The TNT structure, function, related infectivity, and role in viral amplification are the focus of our proposal.
TNTs are long-range (30-500 µm) cell membrane projections that mediate the direct transfer of organelles and signaling molecules between connected cells. TNTs are not expressed in healthy individuals, but upon disease, TNT proliferates. We identified that HIV infection and reactivation induce TNT formation. TNTs transport HIV and/or viral components that result in the targeted cells' infection as demonstrated in vitro and in vivo. Our data indicate that TNT-mediated HIV transmission is 10-100-fold more efficient than a cell-free virus. TNTs, like VS, protected the virus from neutralizing antibodies, and ART and promote multiple strain infections. Our hypothesis is that “HIV highjack TNT formation and communication to enable viral infectious material to spread between TNT connected cells during early stages of infection and reactivation.” We expect to identify the mechanism by which TNT mediates the transport of viral components from a few HIV-infected cells into uninfected cells. But also, apply this research to neurological diseases such as Tau pathologies where TNTs are used to transmit aggregated proteins.