HIV-associated neurocognitive disorder--pathogenesis and prospects for treatment

Abstract

In the past two decades, several advancements have improved the care of HIV-infected individuals. Most importantly, the development and deployment of combination antiretroviral therapy (CART) has resulted in a dramatic decline in the rate of deaths from AIDS, so that people living with HIV today have nearly normal life expectancies if treated with CART. The term HIV-associated neurocognitive disorder (HAND) has been used to describe the spectrum of neurocognitive dysfunction associated with HIV infection. HIV can enter the CNS during early stages of infection, and persistent CNS HIV infection and inflammation probably contribute to the development of HAND. The brain can subsequently serve as a sanctuary for ongoing HIV replication, even when systemic viral suppression has been achieved. HAND can remain in patients treated with CART, and its effects on survival, quality of life and everyday functioning make it an important unresolved issue. In this Review, we describe the epidemiology of HAND, the evolving concepts of its neuropathogenesis, novel insights from animal models, and new approaches to treatment. We also discuss how inflammation is sustained in chronic HIV infection. Moreover, we suggest that adjunctive therapies--treatments targeting CNS inflammation and other metabolic processes, including glutamate homeostasis, lipid and energy metabolism--are needed to reverse or improve HAND-related neurological dysfunction.

Figure 1. Timeline of advances in neuro-AIDS research

Since the discovery of AIDS in 1981 and HIV in 1983, important advances have been made in research into and the prevention and treatment of HIV-associated neurocognitive disorder (HAND). AZT, azidothymidine; CART, combination antiretroviral therapy; HNRC, HIV Neurobehavioral Research Center; MACS, Multicenter AIDS Cohort Study; UCSD, University of California San Diego.

Figure 2. More-effective therapies have reduced the severity of HIV-associated the severity of HIV-associated neurocognitive disorders

Since the introduction of combination antiretroviral therapies (CARTs) in 1996, the proportion of HIV+ individuals with neurocognitive symptoms has remained unchanged, but the proportion of people with severe symptoms has declined so that HIV-associated dementia (HAD) is much less common and asymptomatic neurocognitive impairment (ANI) now accounts for the majority of cases. MND, mild neurocognitive disorder. Adapted from McArthur, J. C. et al. Ann. Neurol. 67, 699–714 (2010).

Figure 3. Neuropathogenic mechanisms that contribute to HIV-associated neurocognitive disorders

HIV-infected macrophages and microglial cells release neurotoxic viral proteins that trigger astrocyte activation, which results in increased glutamate release and reduced glutamate uptake. Elevated extracellular glutamate levels cause neuronal bioenergetic disturbances that lead to aberrant synaptodendritic pruning and neuronal injury. Moreover, systemic inflammation and microbial translocation products lead to microglial activation and increased production of chemokines and cytokines that contribute to neuronal injury. Adapted from Williams, D. W. et al. Curr. HIV Res. 12, 85–96 (2014).