AIDS

Abstract

Infection with human immunodeficiency virus (HIV)-1 not only targets and compromises cells of the immune system and eventually causes AIDS but also triggers a variety of neurological problems that can culminate in frank dementia. Several lines of evidence suggest that HIV-1 strikes at the brain in at least two ways: (i) by causing toxicity leading to neuronal injury and death and (ii) by impairing neurogenesis without killing neural precursors. Both of the pathogenic mechanisms share the involvement of neuroinflammatory mediators, and both processes seem to be influenced by host and viral factors, including the interferon response, age and viral subtypes, as well as treatment and comorbidity factors, such as drug abuse. Development of both HIV-associated neurocognitive disorders (HAND) and AIDS goes hand-in-hand, and despite viral control and life-prolonging effects of combination antiretroviral treatments (cART), neuroinflammation and concomitant activation of macrophages and microglia accompany the continued development of HAND in HIV patients. Besides intact HIV-1, six of its proteins have been linked to neuronal injury. Experimental evidence supports two different, but not exclusive, hypotheses of how HIV-1 causes neuronal damage in the brain. The "direct injury" hypothesis proposes that viral proteins directly compromise neurons, whereas the "indirect" or "bystander effect" hypothesis states virus infection and viral components trigger in macrophages and microglia and astrocytes the production of neurotoxins that injure neurons. HIV-1 and its six neurotoxic protein components can trigger a plethora of cellular responses and signaling mechanisms. However, it appears that the HIV-1 and its viral components cause neurotoxicity via converging mechanisms even if the virus and each component may start out their pathogenic mechanism by interacting with different host cell factors. Converging mechanisms in HIV neurotoxicity include neuroinflammation, MAPK signaling, altered gene expression, oxidative stress, interference with the cell cycle machinery and autophagy, excitotoxicity, synaptic injury, and, ultimately, neuronal apoptosis.