**1. Introduction**

The human immunodeficiency virus (HIV) has a predilection to infect the nervous system. It is therefore neurotropic [1–3]. This correlates clinically with the fact that neurological symptoms occur commonly and during all stages of HIV infection [2, 3]. Between 40 and 70% of people infected with HIV will develop clinically symptomatic neurology, and at autopsy, 90% have neurological disease [2].

HIV-1, once it enters the human body, spreads hematogenously. The entry into the brain compartment is through blood-derived macrophages. The mechanisms are not completely understood

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

but are proposed to involve cell trafficking across the blood brain barrier. The blood-derived infected macrophages or lymphocytes adhere to the vascular endothelium and then are thought to pass through it by EMPERIPOLESIS [2]. The trafficking-infected cell then transmits the virus to microglial cells or perivascular macrophages on the brain side of the blood brain barrier, a "Trojan horse" type of mechanism. The virus in these infected microglia then undergo productive replication and infects other microglia spreading the infection. Astrocytes are likewise infected but replication within these cells is incomplete or nonproductive and forms a reservoir. Neurons and oligodendrocytes are not directly infected by the virus and damage to these cells occurs by chemokines and cytokines released from the infected microglia and astrocytes [2, 3].

The nervous system is also affected by HIV through indirect mechanisms that involve immunosuppression-related opportunistic disease and metabolic complications of systemic HIV

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The spectrum of HIV related or associated neurological disorders is broad and any part of the neural axis may be affected. Neurological complications of HIV are very *stage-specific* and relate to altered immune responses and deficiencies of cell mediated immunity–*dysregulation* 

*Metabolic diseases* that result from dysfunction of other organ systems and *toxic* complications of drugs used to treat the HIV infection and its complications also cause neurological compli-

**1.** impairment of protective defenses with reduction in CD4 lymphocytes and macrophages. This occurs with late infection and is the most important determinant of neurological dis-

**2.** elaboration of certain cytokines also determine neurological disease in late infection **3.** autoimmune reactions in early HIV infection determine some neurological disorders

**2.** Immunosuppression: opportunistic infections/neoplasms (late phase HIV infection)

**1.** Autoimmune disease (early and middle phases of HIV infection)

Acute phase encephalitis, neuropathies (AIDP) Subacute and chronic inflammatory neuropathies Acute disseminated encephalomyelitis (ADEM)

Progressive multifocal leukoencephalopathy (PML)

HIV-related neurocognitive disorders (HAND)

infection and treatment with antiretroviral agents [1–3].

**2. Neurological disease classification**

cations, especially in late stage HIV infection [1–3].

Dysregulation of immunity is caused by:

*of immunity* [1, 2].

ease in HIV

**2.1. Immune dysregulation**

Cerebral toxoplasmosis

Cryptococcal meningitis

CMV encephalitis

**3.** HIV driven

Primary CNS lymphoma (PCNSL)

Distal sensory polyneuropathy

The essential mediators of HIV-related CNS disease are the microglial soluble mediators, including quinolinic acid, TNF-alpha, IL-1 beta (**Figure 1**). Quinolinic acid binds to the NMDA receptor and increases calcium uptake with resultant activation of apoptotic mechanisms. TNF-alpha damages myelin and IL-1 beta stimulates astrocytes. Astrocytes produce nitric oxide and colony stimulating factors that feed back on microglia [2, 3].

The net result of this inflammatory cascade is an encephalitis, which is pathologically characterized by white matter pallor, neuronal loss, and astroglial reaction. This initiates and is the basis of primary HIV disease or as is commonly referred to as direct HIV infection of the nervous system.

**Figure 1.** Neuropathophysiology of HIV infection in the Brain.

The nervous system is also affected by HIV through indirect mechanisms that involve immunosuppression-related opportunistic disease and metabolic complications of systemic HIV infection and treatment with antiretroviral agents [1–3].
