Abstract Synaptodendritic neuronal injury is emerging as an important mediator of cognitive deficits in HIV-positive individuals. Nevertheless, the molecular and cellular mechanisms of how HIV causes axonal pruning are still far from established. This precludes effective treatment of the neurological complications. Recent findings report that the HIV soluble envelope protein gp120 is endocytosed into neurons and binds to tubulin ?-3 (TUBB3), a major component of neuronal microtubules (MTs), which are essential for neuronal function. Neurons that endocytose gp120 exhibit neurite retraction and activation of caspase-3, raising the hypothesis that the endocytic process and the binding to TUBB3 are crucial for gp120-mediated neuronal injury. In this exploratory proposal, we will test this hypothesis by examining gp120-neurotoxicity in the presence of compounds that displace gp120 from binding to TUBB3 (AIM 1). Gp120 internalization is CXCR4 receptor mediated. To discriminate between chemokine receptor signaling and binding to MTs as a mechanism of neurotoxicity, experiments in AIM 2 will test whether the delivery of gp120 inside neurons by mesoporous silica nanoparticles is neurotoxic. The characterization of how viral proteins interact with the neuronal cytoskeleton and negatively affect mature synapses will provide considerable insights toward understanding the mechanism underlying HIV-associated neurocognitive disorders. If successful, this proposal will establish that gp120, after its internalization, injures neurons by binding to and damaging neuronal MTs. This is a novel mechanism of gp120 neurotoxicity that, if proven, will help in the design of compounds that will inhibit the neurotoxic effect of gp120.