Novel mechanisms of central nervous system damage in HIV infection

Abstract

Human immunodeficiency virus-1 infection of the central nervous system is an early event after primary infection, resulting in motor and cognitive defects in a significant number of individuals despite successful antiretroviral therapy. The pathology of the infected brain is characterized by enhanced leukocyte infiltration, microglial activation and nodules, aberrant expression of inflammatory factors, neuronal dysregulation and loss, and blood-brain barrier disruption. Months to years following the primary infection, these central nervous system insults result in a spectrum of motor and cognitive dysfunction, ranging from mild impairment to frank dementia. The mechanisms that mediate impairment are still not fully defined. In this review we discuss the cellular and molecular mechanisms that facilitate impairment and new data that implicate intercellular communication systems, gap junctions and tunneling nanotubes, as mediators of human immunodeficiency virus-1 toxicity and infection within the central nervous system. These data suggest potential targets for novel therapeutics.

Keywords: AIDS; chemokines; dementia; gap junctions; inflammation; nanotubes.

Figure 1

Mechanisms of HIV-mediated CNS damage. HIV infection of peripheral blood mononuclear cells, particularly monocytes, leads to enhanced expression of adhesion molecules and chemokine receptors such as CCR2. This results in increased transmigration of infected cells. HIV enters the CNS through a “Trojan horse” mechanism, crossing the blood–brain barrier, formed by endothelial cells and astrocyte end feet, within infected monocytes. Once inside the CNS, infected monocytes can differentiate into macrophages and secrete a number of inflammatory mediators, particularly chemokines such as CCL2 that further enhance transmigration of immune cells across the blood–brain barrier. HIV infection of macrophages increases the numbers of TNT that connect with other macrophages. HIV or HIV proteins may travel within or on TNT, facilitating viral spread. Infected cells also secrete viral proteins such as gp120 and tat that are toxic to neurons. HIV can infect astrocytes at low levels. Infected astrocytes transfer signals to neighboring uninfected astrocytes and neurons. These signals are transferred through gap junctions and result in apoptosis (X) in both astrocytes and neurons. Astrocytes are necessary for the metabolic maintenance of neurons. Thus, the astrocyte loss and dysfunction that occurs with HIV infection also results in metabolic dysregulation and neuronal toxicity. Abbreviations: CNS, central nervous system; EC, endothelial cells; HIV, human immunodeficiency virus; TNT, tunneling nanotubes.