ASTROCYTE-ENDOTHELIAL INTERACTIONS: IMPLICATIONS FOR HIV-ASSOCIATED NEUROCOGNITIVE DISORDER

Abstract

During the course of HIV-1 disease, virus neuroinvasion occurs as an early event, within weeks following infection. Intriguingly, subsequent central nervous system (CNS) complications manifest only decades after the initial virus exposure. In the current era of combined anti-retroviral therapy (cART), while the virus replication in the periphery is brought under complete control, in the CNS owing to poor drug penetrance, there occurs development of increasing neurocognitive complications. So while the HIV-infected patients are living longer and have decreased incidence of the disease, the prevalence of HIV-associated neurocognitive disorders (HAND) is actually on a rise. Although CNS is commonly regarded as an immune-privileged site, emerging evidence indicates that innate immunity elicited by the CNS glial cells is a critical determinant for the establishment of protective immunity. Sustained expression of the protective immune responses manifested as increased expression of a mediator, such as platelet-derived growth factor (PDGF), however, can be a double-edged sword. While PDGF has been defined as a neuroprotective immune mediator, in concert with other inflammatory mediators (elicited by HIV or its protein products), it can tip the balance from a protective to a toxic state in the CNS. Herein, we present an overview of some of the essential elements of the cerebral innate immunity in HIV neuropathogenesis including the role that platelet-derived growth factor (PDGF) released from astrocytes has in exacerbating HAND. Out of the various PDGF isoforms, PDGF-BB is critical for astrocytes and hence is the focus of our study. PDGF-BB exposure to astrocytes results in astrogliosis and release of the chemokine monocyte chemotactic protein-1 (MCP-1), the two hallmark features of HAND. To further understand these observations and explore the role of PDGF-BB regulation in HAND, our central hypothesis is that exposure of astrocytes to HIV transactivating protein Tat results in the release of growth factors such as PDGF-BB, which could ultimately lead to enhanced astrogliosis and blood-brain barrier(BBB) disruption. The aim of this study was to explore the mechanism of PDGF-BB regulation in astrocytes as it relates to HAND pathogenesis.