Abstract
Human immunodeficiency virus type-1 (HIV-1)-associated neurocognitive disorder (HAND) remains an important neurological manifestation that adversely affects a patient’s quality of life. HIV-1 matrix protein p17 (p17) has been detected in autoptic brain tissue of HAND individuals who presented early with severe AIDS encephalopathy. We hypothesised that the ability of p17 to misfold may result in the generation of toxic assemblies in the brain and may be relevant for HAND pathogenesis. A multidisciplinary integrated approach has been applied to determine the ability of p17 to form soluble amyloidogenic assemblies in vitro. To provide new information into the potential pathogenic role of soluble p17 species in HAND, their toxicological capability was evaluated in vivo. In C. elegans, capable of recognising toxic assemblies of amyloidogenic proteins, p17 induces a specific toxic effect which can be counteracted by tetracyclines, drugs able to hinder the formation of large oligomers and consequently amyloid fibrils. The intrahippocampal injection of p17 in mice reduces their cognitive function and induces behavioral deficiencies. These findings offer a new way of thinking about the possible cause of neurodegeneration in HIV-1-seropositive patients, which engages the ability of p17 to form soluble toxic assemblies.
Highlights
Human immunodeficiency virus type-1 (HIV-1)-associated neurocognitive disorder (HAND) remains an important neurological manifestation that adversely affects a patient’s quality of life
One possibility contributing to HIV-1-associated neurocognitive disorder (HAND) include the presence of low level viremia in the central nervous system (CNS) that may chronically drive neurodegeneration, neurons are refractory to HIV-1 infection
We show that p17 significantly inhibits pharyngeal contractions in C. elegans to an extent comparable to other amyloidogenic proteins, and that its toxic effect is strictly related to its conformational state
Summary
Data on p17 expression in CNS tissue of patients with AIDS revealed the presence of the viral protein in potentially HIV-1-infected elements, such as mature macrophages and microglia cells[19, 21, 50]. The exposure of hydrophobic residues on the surface of p17 oligomers may be important for the dysfunction caused by the protein on the C. elegans pharynx, as suggested by the lower effect when worms were fed with larger assemblies instead of small oligomers All these findings support that the toxic effect of p17 may contribute to the toxicity of p17 in the HIV-infected brains. The characterisation of the morphology and spatial extent of the assemblies produced in vitro by the HIV-1 matrix protein p17 indicate that the protein can form small oligomers that grow rapidly with time and form annular or rosary-like structures before forming prefibrillar soluble structures These assemblies are toxic in vivo in C. elegans and induced neurocognitve disorders in mice. Our findings offer a new way of thinking about the possible cause of neurodegeneration in HIV+ patients, which engages the ability of p17 to form soluble toxic assemblies and put forward innovative hints for the development of novel pharmacological strategies
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