Neuronal toxicity in HIV CNS disease

Abstract

HIV enters the brain during the early stages of initial infection and can result in a complicated array of diverse neurological dysfunctions. While neuronal injury and loss are at the heart of neurological decline and HIV-associated neuropathology, HIV does not productively infect neurons and the effects of HIV on neurons may be described as largely indirect. Viral proteins released from infected cells in the CNS are a well-characterized source of neuronal toxicity. Likewise, host-derived inflammatory cytokines and chemokines released from infected and/or activated glial cells can damage neurons, as well. Newly identified host-virus interactions and the current state of our knowledge regarding HIV-associated neuronal toxicity will be addressed in this review. Aspects of HIV-associated neurotoxic mechanisms, patterns of neuronal damage, viral effects on neurotrophic signaling, clade variations and comorbid substance abuse will be discussed. Recent advances in our understanding of the impact of HIV infection of the CNS on neuronal dysfunction and cell death will also be highlighted.

Keywords: CNS; HIV-associated neurocognitive disorders; blood–brain barrier; cART; excitotoxicity; inflammation; neurons; synaptodendritic.

Figure 1. Simplified gene map of HIV-1 indicates reported effects of viral gene proteins on cells of the CNS

HIV genes encode proteins that can be divided into three classes: structural: Gag, Pol (polymerase) and Env (envelope gp120, gp41); regulatory: Tat (transactivator of transcription) and Rev (regulatory for expression of viral proteins); and accessory: Vif (viral infectivity factor), Vpu (viral protein U), Vpr (viral protein R) and Nef (negative factor). gp: Glycoprotein; iNOS: Inducible nitric oxide synthase; LTR: Long terminal repeat. Reproduced with permission from [30].

Figure 2. HIV proteins and host-derived inflammatory factors damage human neurons

(A) Human primary neurons exposed to media from peripheral blood mononuclear cells not infected with HIV show normal morphology with intact process branching and normal cell bodies. (B) Neurons exposed to the supernatant from peripheral blood mononuclear cells infected with HIV show abnormal branching with beading (arrowhead), dystrophic process extensions (arrow) and degenerating cell bodies. Magnification = ×40.

Figure 3. Immunofluorescence labeling of human brain tissue showing loss of synaptodendritic markers in HIV encephalitis

(A) Frontal cortex from an HIV patient with no CNS alterations, showing normal distribution of dendrites (microtubular-associated protein 2: green) and axons (neurofilament: red). (B) Frontal cortex from an HIV encephalitic patient showing loss of immunolabeling for dendrites (microtubular-associated protein 2: green) and axons (neurofilament: red). Magnification = ×40.