Direct and indirect mechanisms of HIV-1 neuropathogenesis in the human central nervous system.

Abstract

HIV-1 infection of the central nervous system (CNS) can manifest itself in a wide range of clinical symptoms and pathological signs. The neuropathology associated with CNS invasion of HIV-1 includes macrophage infiltration, inflammation, astrocytosis, and ultimately, neuronal damage and cell loss. HIV-1 has the ability to rapidly penetrate the brain of most infected individuals, but results in a severe neurological disease in only a subset. It is estimated that approximately 20% to 30% of adults with advanced HIV infection will develop neurological impairments, and a significantly higher percentage of pediatric AIDS cases will demonstrate developmental abnormalities (1). AIDS related neurological complications have been documented as AIDS dementia complex (ADC), HIV-1 associated dementia (HAD), and HIV-1 related cognitive-motor complex as well as CNS lymphoma and opportunistic infections. In a small percentage of cases, the emergence of neurologic symptoms may actually presuppose a diagnosis of AIDS. As such, ADC, first recognized in 1986, has since been added to the list of the CDC’s AIDSdefining conditions. The clinical manifestations of cortical and subcortical neuron loss in adult ADC include impaired memory function, motor deficits, and eventual dementia in the absence of any other opportunistic infection (1). CNS complications are particularly evident in children, as affected infants and children are slower to develop, and will exhibit motor abnormalities, followed by a rapidly progressing encephalopathy. A differential diagnosis of ADC can be difficult because the pathology and clinical symptoms mimic those of opportunistic CNS viral infections such as progressive multifocal leukoencephalopathy (PML) and cytomegalovirus (CMV) infection. Although the symptoms are well recognized, the biological and molecular mechanisms responsible for the pathology and the occurrence of mild or severe dementia are unclear. HIV-1 is capable of productively infecting macrophages and monocytes, but only rarely infects neurons or astrocytes in situ (2). Furthermore, the percentage of infected cells is low in comparison to the total number of cells in the brain. The paradox, then, is how such a limited number of productively infected cells can lead to the severe neurologic deficits observed in AIDS encephalopathy. Also related to this is the structural and functional sequestration of the CNS from the body’s immune system. Since there is no humoral immune response mounted against HIV-1 infection in the brain, it has been theorized that infected astrocytes may serve as a potential reservoir for virus in its latent