Today, it is accepted that human immunodeficiency virus (HIV) entry and spread to other cells is mediated by sequential binding of viral envelope proteins to CD4 and CCR5 or CXCR4, two chemokine co-receptors. This binding trigger fusion of the viral membrane with the host cell membrane allowing the virus is internalized. Once inside the cell, the HIV cell cycle is the well-known mechanism of viral cell infection and subsequent viral spread into uninfected cells and these different steps are the basis for the current antiretroviral treatments (ART) available. However, and despite the efficiency of ART to reduces viral replication viral rebound and cellular reservoirs still remain an important unsolved issue. Our data suggest that in addition to the well-known viral cell cycle described above. Tunneling nanotube (TNT) also can play a key role as an alternative pathway for viral infection and spread, by an intracellular mechanism, that do not require extracellular budding and reentry of the virus, suggesting that this pathway probably is insensitive to ART that blocks these steps. To demonstrate that intracellular communication plays a key role in the pathogenesis of HIV, our group identity that another intracellular communication system, gap junctions, contribute to amplify apoptosis and toxicity between communicated astrocytes. Our group becomes a lead in intracellular communication systems in the context of HIV infection and NeuroHIV. Thus, our current proposal will examine the mechanism by which TNT serve an alternative pathway of early viral infection and spread between connected cells. Based on in the mechanisms identified in our proposed aims we will test potential drugs that block viral spread through TNT. Our current hypothesis is that TNT formation induced by HIV infection allows HIV to spread between connected cells by an intracellular route without an extracellular component.