Cross-talk between microglia and neurons regulates HIV latency

Area of Science:

• Neuroscience
• Immunology
• Virology

Background:

• HIV-associated neurocognitive disorders (HAND) affect nearly one-third of patients despite effective antiretroviral therapy (ART).
• The precise mechanisms driving HAND remain incompletely understood, particularly the role of HIV latency and reactivation in microglia.

Purpose of the Study:

• To investigate the hypothesis that neurological degeneration in HAND results from periodic HIV emergence from latency in microglia.
• To elucidate the role of neuronal damage and inflammatory signals in modulating HIV expression and neurotoxicity.

Main Methods:

• Utilized a cellular co-culture system with neurons and HIV-infected human microglia (hμglia/HIV).
• Employed induced pluripotent stem cell (iPSC)-derived neurons (cortical, dopaminergic, motor) and a clonal hμglia/HIV population (HC69).
• Modeled neurotoxicity using methamphetamine (METH) and poly(I:C) to assess their impact on HIV expression and neuronal damage.

Main Results:

• Healthy neurons initially silenced HIV in microglia, while damaged neurons induced HIV expression.
• Co-culture of HIV-expressing microglia with neurons led to significant dendritic pruning (MAP2 staining reduction).
• METH and poly(I:C) synergistically induced HIV expression and dendritic damage, mediated by the σ1 receptor.

Conclusions:

• Cross-talk between neurons and microglia modulates HIV expression; HIV impairs this interaction, leading to uncontrolled microglia-mediated neurotoxicity.
• HIV reactivation from latency in microglia, influenced by neuronal status, is a key driver of HAND.
• Understanding these interactions is crucial for developing targeted therapies for HAND.