HIV-1 clade-specific differences in the induction of neuropathogenesis

Area of Science:

• Neuroscience
• Virology
• Immunology

Background:

• Human immunodeficiency virus (HIV)-associated dementia (HAD) is more prevalent and severe in individuals infected with HIV clade B compared to clade C.
• Previous research on neuropathogenicity differences has primarily used in vitro viral protein studies, lacking animal model validation.

Purpose of the Study:

• To investigate the neuropathogenesis of different HIV-1 clades using an animal model.
• To determine if viral genetic differences between clades influence the severity of HIV-induced brain disease.

Main Methods:

• Utilized the severe combined immune deficiency (SCID) mouse model of HIV encephalitis.
• Inoculated SCID mice intracranially with macrophages infected with representative clade B (HIV-1(ADA)) or clade C (HIV-1(Indie-C1)) isolates.
• Conducted cognitive tests and histopathological analyses on infected mice.
• Performed in vitro experiments to assess monocyte recruitment by infected macrophages.

Main Results:

• Mice exposed to HIV-1 clade C exhibited fewer memory errors compared to those exposed to clade B.
• Histopathology revealed greater astrogliosis and neuronal network damage in clade B-exposed mice.
• In vitro, clade C-infected macrophages showed poorer monocyte recruitment than clade B-infected macrophages, dependent on HIV-1 Tat and CCL2.

Conclusions:

• This study provides the first animal model evidence that genetic differences between HIV-1 clades impact disease severity.
• Viral clade differences significantly influence neuropathogenesis, affecting cognitive function and neuronal integrity.
• Identified monocyte recruitment, mediated by HIV-1 Tat and CCL2, as a key factor in clade-specific neuropathogenesis.