20 (Fig. 1c, d) [226, 251]. Astrocyte endfeet prominently line blood vessels in healthy tissue (Fig. 1b) and become hypertrophic during encephalitis (Fig. 6a) and surround perivascular clusters of inﬂammatory cells (Fig. 1c, d), and experimental disruption of perivascular astrocytes leads to widespread inﬁltration of lymphocytes and other inﬂam- matory cells into CNS parenchyma [251]. Reactive astrocytes also play a role in the potential neurological complications resulting from direct HIV-1 infection of the brain, which commonly results from ‘neurotropic’ strains of HIV-1 gaining entry to the CNS. Such strains usually target microglia or macrophages (not astrocytes), and may gain entry to the brain by entering it within infected T-lymphocytes (the ‘Trojan horse’ hypothesis of CNS infection). This can eventually result in cognitive impairment, initially mild, which can progress to HIV-associated dementia (abbreviated as HAD, formerly described as AIDS dementia complex/ADC). Despite the relative efﬁcacy of highly active antiretroviral therapy in controlling AIDS, no treatment has to date been found that consistently moderates the pathogenic events important in the evolution of HAD or that achieves neuronal protection from the effects of the virus. The majority of viral repli- cation in the brain occurs in microglia. Astrocytes can be infected but do not appear to serve as sites of viral repli- cation. Infected microglia and astrocytes are the main cause of neurotoxicity, which appears to result indirectly from signals exchanged between the two cell types, resulting in the secretion of potentially toxic molecules within the CNS parenchyma, both cerebral neocortex and white matter. Astrocyte dysfunction with loss of neuro- supportive and neuroprotective functions, in particular disruption of glutamate homeostasis leading to synapse dysfunction and excitotoxicity are regarded as the most likely mechanisms in mediating HIV related cognitive impairment and neurodegeneration [100, 253]. HIV-1 infection of the CNS is arguably at present the most common form of brain viral infection. However, numerous other viruses can cause neurological morbidity and even mortality in individuals with a normal immune system, or in those who are immunosuppressed, regardless of whether said immunosuppression is the result of AIDS, aggressive therapy for solid tumors or hematologic malignancy, iatrogenic immunosuppression in a patient with organ or bone stem cell transplantation, or other (e.g., congenital immunodeﬁciency) disease. Almost all viruses, as with HIV-1 (see above), manifest tropism for various cell types within the brain or spinal cord; that tropism may include the astrocyte. Some of the herpes viruses, e.g., Herpes simplex and cytomegalovirus (the latter being a 123 Acta Neuropathol (2010) 119:7–35 Fig. 6 Reactive astrogliosis in two disorders with seizures. a High magniﬁcation image of cerebral cortex from an individual with Rasmussen encephalitis (RE). Immunohistochemical staining for GFAP shows moderate reactive astrogliosis that is especially prominent around small blood vessels. Note the intensely stained and hypertrophic astrocytic foot processes extending to and lining the adventitia of microvessels. b, c High magniﬁcation images of a resection specimen from an individual with severe seizures associated with severe focal cortical dysplasia stained for H&E (b) or GFAP (c). b In this unique case, abundant Rosenthal ﬁbers were found throughout the resection specimen, especially in the subpial regions (arrows) and around blood vessels (arrowheads). The density of the Rosenthal ﬁbers suggested the diagnosis of ‘focal’ Alexander’s disease. However, testing of the GFAP gene revealed no mutations (for details, see [111]). c Comparable section to b showing abundant GFAP immunoreactive astrocytes and associated Rosenthal ﬁbers (arrows). Scale bars a 10 lm, b 20 lm, c 15 lm