HIV and the Nervous System

Abstract

Human immunodeficiency virus (HIV) infection in the pre‐antiretroviral drug era was known to cause a variety of neurological syndromes, including HIV‐associated dementia, myelopathy, peripheral neuropathy, opportunistic infections of the nervous system and primary central nervous system (CNS) lymphoma. The era of efficient combined antiretroviral treatment has led to a shift in the nature of these syndromes, yet HIV infection is still a major cause of neurological disease, typically causing a more chronic effect, as is the case in mild cognitive impairment attributed to the virus. The mechanisms underlying this chronic effect are related to the CNS being a viral reservoir, as HIV does not directly infect neurons but does reside in different cells of the nervous system such as macrophages, microglia and astrocytes, implicating neuronal injury using neurotoxic viral factors and initiating processes of neuroinflammation and neurodegeneration. In addition, the antiretroviral treatment itself is responsible for some aspects of neurological morbidity, mainly peripheral neuropathy and possible CNS manifestations of immune reconstitution inflammatory syndrome after treatment is initiated. Key Concepts HIV‐1 invades the nervous system during early infection, frequently infecting perivascular macrophages, microglia and astrocytes. The central nervous system is a potential reservoir for HIV‐1, challenging eradication and leading to chronic neurological complications despite antiretroviral treatment. Neurotoxic viral factors, neuroinflammation and neurodegeneration are the main mechanisms underlying neuropathogenesis of HIV‐1. The main neurotoxic viral proteins are gp120, transactivator of transcription (Tat), Vpr and Nef. CNS‐infiltrating monocytes are the primary blood‐derived contributors to neuroinflammation in HIV infection, leading to gliosis and astrocytosis and the release of inflammatory cytokines such as TNF‐α, IL‐1β and interferons. Neurodegeneration has been shown to be mediated by DNA damage and mitochondrial abnormalities but also by other processes including protein aggregates, cellular senescence and epigenetic alterations. The major neurological syndrome seen in cases of treated HIV infection is mild neurocognitive impairment. In untreated patients, opportunistic infections, HIV‐myelopathy and primary CNS lymphoma and are the main causes of neurological disease. Antiretroviral treatment can also lead to a neurological sequela, whether due to direct neurological side effects of drugs or due to the indirect consequences of immune reconstitution inflammatory syndrome (IRIS).