Investigation of the Role of the p75 Neurotrophin Receptor in HIV-1 gp120-associated Synaptic and Neural Injury

Abstract

Human immunodeficiency virus type 1 (HIV) remains a tenacious global pandemic nearly 40 years after its initial description in humans, currently affecting greater than 37 million individuals worldwide. Despite significant advancements in combined antiretroviral therapies over the last twenty-five years, as many as 50% of all people living with HIV (PLWH) will experience some degree of neurological or neuropsychological impairment in their lifetime. Together, these HIV-associated neurocognitive disorders (HAND) represent a major obstacle in the continued management of HIV and contribute strongly to a decreased quality of life in PLWH. Evidence from both human post-mortem tissue and animal models indicates that attenuated, but persistent production of viral proteins in the CNS is a major factor driving neuropathological changes in the HIV-positive CNS. These proteins, including the neurotoxic HIV envelope glycoprotein gp120, serve to interrupt multiple glial and neuronal processes and promote atrophic morphological changes. Examination of the effect of gp120 upon the cellular systems involved in neuronal health and resilience to neurotoxic molecular stimuli is likely to yield mechanistic explanations for cognitive impairments manifest in PLWH and aid in the development of therapeutic strategies.

In this dissertation, we examine the contribution of the p75NTR neurotrophin receptor (NTR) in transducing the neurotoxic effect of gp120 upon the neurotrophin-NTR system. We investigate our broad hypothesis by using an animal model of HAND, the gp120 transgenic (tg) mouse, which has been crossed with p75NTR knockout mice to generate gp120tg mice with an altered expression of p75NTR. We assess our endpoints of interest in this model through biochemical, histological, behavioral, and imaging approaches. Our series of experiments suggest that gp120 is a major contributor to an age-dependent dysregulation of neurotrophins and their receptors, which together promote atrophic processes at both the synaptic and neuron levels through p75NTR. These results indicate that future therapeutic interventions targeting p75NTR may serve as a viable strategy for neurological impairments in PLWH.