Abstract Despite antiretroviral therapy (ART), HIV can cause cognitive and mental health disorders, referred to as HIV- associated neurocognitive disorders (HAND). HAND pathology, which is characterized by synaptodendritic damage, resembles that observed in aging brain. At present, there are no effective treatments for HAND. In addition, it has been suggested that anti-retroviral therapy (ART) impairs neuronal function; thus, the identification of new mechanisms that can lead to a reduction of HIV-mediated neuropathology is important. The major goal of this project is to discover the biological mechanisms whereby HIV reduces dendrites. Our preliminary data show that the cerebrospinal fluid (CSF) and postmortem brains of people living with HIV (PLWH), whose neurocognitive performance is reduced, have a higher content of microtubule-associated protein 2 (MAP2), when compared to cognitively normal PLWH. MAP2, which is highly enriched in dendrites, binds to microtubules (MTs) and plays a key role in their formation and elongation, and helps neuronal trafficking. However, MAP2 has different isoforms that, when accumulate in neurons, they promote impairment of MTs function and dendritic degeneration. HIV could directly alter MAP2 levels or use viral proteins to impair the function of MTs. Because the HIV-mediated loss of dendrites is experimentally reproducible by the envelope glycoprotein gp120, we hypothesize that HIV affects the overall function of dendritic MTs by a gp120- dependent mechanism which encompasses an alteration of MAP2 binding to MTs. Two Specific Aims are proposed to test this hypothesis. In Aim 1, we will examine the mechanisms whereby HIV/gp120 alters MAP2. In Aim 2, we will use various approaches to reduce or enhance MAP2 isoforms and examine their role in dendritic injury. A better understanding of these mechanisms is instrumental for drug development to reduce the incidence of HAND.