Synaptic dysfunction in human immunodeficiency virus type-1-positive subjects: inflammation or impaired neuronal plasticity?

Abstract

Many people infected with the human immunodeficiency virus type-1 (HIV) exhibit mild or severe neurological problems, termed HIV-associated neurocognitive disorder (HAND), even when receiving antiretroviral therapy. Thus, novel adjunctive therapies must be developed to overcome the neurotoxic effect of HIV. New therapies require a better understanding of the molecular and cellular mechanisms of HIV-induced neurotoxicity and the risk factors that, besides inflammation and T-cell depletion and drugs of abuse, render the central nervous system (CNS) a target of HIV-induced neurotoxicity. HIV appears to impair neuronal plasticity, which refers to the innate ability of the CNS respond to injury and promote recovery of function. The availability of brain-derived neurotrophic factor (BDNF), a potent neurotrophic factor that is present in abundance in the adult brain, is essential for neuronal plasticity. BDNF acts through a receptor system composed of Trk and p75NTR. Here, we present experimental evidence that some of the clinical features of HIV-mediated neurological impairment could result from altered BDNF/TrkB/p75NTR regulation and function.

Fig. 1

Schematic diagram of HIV proteins and their function. Adapted from [12].

Fig. 2

HIV induces synaptic simplification through gp120. A) Cortical neurons exposed to a physiological environment (B) in which BDNF and other neurotrophic factors, released in an activity-dependent manner, maintain an intact neuronal architecture. C) Image of neurons exposed to HIV or gp120 in which (D) the lack of trophic support evokes short processes and elimination or pruning of processes that eventually culminate in apoptosis. Scale bar, 10 μm.

Fig. 3

Proposed mechanisms of HIV-mediated synaptic simplification. (A) HIV-negative synapse. Under physiological conditions, proBDNF is released in an activity-dependent manner and is processed to mature BDNF either intracellularly by furin or extracellularly by plasmin and matrix metalloproteinases (MMPs). Plasmin is generated from plasminogen by released tissue plasminogen (tPA). (B) HIV-positive synapse. Gp120, shed from HIV, binds to chemokine receptors. This leads to reduced intracellular processing of proBDNF which appears to occur through a decrease in furin and/or prohormone convertase (PC1/3) synthesis/activity [82]. (C) Extracellular BDNF/proBDNF. Mature BDNF binds with high affinity to its cognate receptor TrkB and low affinity to p75NTR. This binding promotes synaptic plasticity through activation of ERK and/or PI kinase. By contrast, released proBDNF binds with high affinity to p75NTR/sortilin which, in turn, activates degeneration of p75NTR-positive neurons through a c-Jun N-terminal kinase (JNK)-mediated mechanism.