HIV-Associated Neurocognitive Disorders in the Era of Highly Active Antiretroviral Therapies

Beau Ances, MD, PhD


October 13, 2008


The prevalence of HIV infection worldwide is greater than 40 million people[1]; in the United States, over 1 million people are infected. HIV-associated neurocognitive disorders (HAND) -- progressing in disability from asymptomatic neurocognitive impairment (ANI) to HIV-associated mild neurocognitive disorder (MND) to HIV-associated dementia (HAD) -- have been recognized as common sequelae of infection.

Early in the epidemic, more than 50% of all HIV-positive patients were diagnosed with HAD. However, the advent and widespread use of initial monotherapy (single agents such as zidovudine) and subsequent combination highly active antiretroviral therapy have changed the face of the disease.[2] The prevalence of HAD has greatly diminished while less severe ANI and MND have risen as individuals live longer with the disease. Consequently, what was once considered an almost uniformly fatal illness is now considered a chronic disease that requires long-term medical management.[3]


HIV enters the brain after the initial infection, most likely soon after seroconversion.[4] One theory of possible viral entrance into the CNS, the Trojan horse hypothesis, involves infected monocyte cells transporting the virus across the blood brain barrier (BBB). After crossing the BBB, these cells transform into infected perivascular macrophages. Another theory, supported by the presence of productive virus in both endothelial and choroid plexus cells,[5] suggests that the cell-free virus directly crosses the BBB. Once the virus enters the brain, macrophages and multinucleated giant cells (fused macrophages and microglia cells) continue to support HIV replication. Neuro-ectodermal derived cells (neurons, astrocytes, and oligodendrocytes) are rarely infected.[3]

Multiple hypotheses exist concerning the dynamics of HIV entry into the brain.[6] One view proposes that the brain is repeatedly exposed to transitory viral contact by infected monocytes. A dynamic equilibrium develops between the brain and periphery (rest of the body). Another theory suggests that the virus within the brain independently evolves under different immunologic and pharmacologic conditions compared with the periphery.[7] Most likely, both situations occur during various stages of viral infection.

Repeated exposures and enhanced viral replication lead to a complex cascade of events within the brain. Since HIV is a retrovirus, it must be reverse transcribed by virally encoded enzymes in order to complete its lifecycle. Although combination antiretroviral therapy (cART) reduces the viral load, low-level replication may still cause dysfunction of nerve cells through an ongoing inflammatory response and astrocytic gliosis. Viral proteins can stimulate brain microglia to produce excess amounts of chemokines, cytokines, and other inflammatory mediators. Typically, these factors regulate cell interactions and are important for normal cellular functioning.[8,9,10] However, at higher concentrations, these inflammatory mediators cause neuronal dysfunction and death.

At autopsy, neuropathologic evaluation of brain tissue from HIV-infected individuals is typically characterized by nonspecific features, such as white-matter pallor, microglial nodules, multinucleated giant cells, and gliosis.[11] These abnormalities are most commonly seen within the central white matter, frontal cortices, basal ganglia, thalamus, and brain stem.[12] Pathologic changes can be quite mild, even in HIV-positive patients with confirmed HAD. No significant correlation exists between cognitive status and neuronal loss, but, instead, dendritic and synaptic damage is often apparent.[13] The overall scarcity of infected cells and the imprecise relationship between the severity of pathology suggest that HAND is multifactorial.[14]


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