Brain damage is a frequent outcome of acquired immunodeficiency syndrome (AIDS), the pathology manifesting in a form of HIV-encephalitis (HIVE). The latter progresses through cognitive impairments, psychomotor abnormalities, including ataxia, towards severe HIV-associated dementia (HAD). In addition to HAD, AIDS also produces HIV-related sensory neuropathies. The combined prevalence of HIV-associated dementia and sensory neuropathies can reach up to 50 per cent in all patients.
Microglia and perivascular macrophages are the principal target for HIV infection of the brain; the virus essentially cannot infect neurones. To infect the cells the HIV uses surface receptors for chemokines (e.g. CD4 or CCR5), which, in the brain parenchyma are mostly associated with microglia. The virus can invade the brain very soon after infection, yet at the latent stages it does not result in any productive infection. There are some indications that during this latent stage, the virus can survive in the brain within the microglial cells, the latter serving as a reservoir (so-called Trojan horse) for HIV, which can reinfect the periphery; this is particularly important in the targeting of antiviral drug therapies. This long-lasting presence of HIV in the brain parenchyma may explain the appearance of CNS-specific strain variances. Viral HAD commences only after onset of AIDS, and then the production of virus in the CNS is very significant.
Histopathologically, HAD is manifested by prominent neuronal death (usually though the apoptotic pathway), the neuronal demise being most prominent in the basal ganglia. The histological hallmark of HIVE/HAD is the appearance of multinucleated giant cells, which represent fused infected microglia/macrophages. Astroglial cells show fewer changes; in fact astrocytes (which also contain surface chemokine receptors) can be readily infected by HIV in vitro; however their infection in the in vivo brain is much less documented.
The neurotoxicity in HIVE results from two principal sources: from viral products and from activated microglia/macrophages. The cytotoxic viral components are glycoprotein 120 (gp120 assists virus binding to plasmalemmal receptors and entry into the cell), tat protein, which acts as a viral transactivator, and Vpr protein. Gp120 kills neurones both in vitro (after being added to culture media) and in vivo (when gp120 was delivered by intra-hippocampal injection). Direct induction of astroglial expression of gp120 in transgenic mice resulted in the development of brain damage similar to HIVE. The actual neurotoxic action of gp120 is mediated through disruption of neuronal Ca2+ homeostasis and Ca2+ excitotox-icity. Gp120 can cause both sustained Ca2+ entry and massive Ca2+ release from the ER stores; the combination of the two causes Ca2+ overload and cell death. Tat protein also induces neuronal apoptosis; the latter can be initiated through Ca2+ dyshomeostasis. Tat protein was reported to induce substantial increases in neuronal [Ca2+]j through activation of NMDA receptors; these [Ca2+]j elevations led to neuronal death; both Ca2+ increase and cell demise can be prevented by NMDA receptor blockers. Tat is also able to trigger Ca2+ signals in microglia through CCR3 chemokine receptors; these Ca2+ signals may assist in spreading the microglial activation. Finally, tat may also stimulate reactive astrogliosis. The Vpr protein triggers apoptotic neuronal death in vitro through yet unknown mechanisms.
The second important source of neuronal death is associated with neurotoxic agents released by activated microglia, which in the case of HIVE fully realizes its pathological potential. In fact the relative HIV production in the brain is not dramatic; it is much less, for example, than production of other neurotropic viruses such as herpes simplex or arboviruses. Therefore, the activated microglia and macrophages may be the leading players in mediating neuronal cell death in HIVE/HAD.
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