Kisspeptin-10 Protects Brain from HIV-Induced Damage and Inflammation

Individuals living with HIV-1 often develop HIV-associated neurocognitive disorders (HAND), a severe complication characterized by blood-brain barrier (BBB) dysfunction and pervasive neuroinflammation. These debilitating neurological issues are largely driven by the HIV-1 Tat protein, which directly damages brain cells and compromises the BBB. Despite existing antiretroviral therapies, effective treatments specifically targeting these neurological sequelae and restoring BBB integrity remain a significant unmet need.

The study revealed that Kisspeptin-10 significantly attenuated HIV-1 Tat-induced blood-brain barrier dysfunction in vitro, leading to a marked restoration of tight junction integrity, which are crucial structures sealing the space between cells. It also significantly reduced neuroinflammation by decreasing the expression of pro-inflammatory cytokines (small proteins that regulate immune responses) and mitigating NF-κB activation, a key regulator of inflammatory genes. Kisspeptin-10 effectively reversed the HIV-1 Tat-induced upregulation of the RhoA/ROCK pathway (a signaling pathway critical for cell structure and function), demonstrating its central mechanism of action in protecting the brain. This inhibition led to a substantial decrease in MMP-9 expression (an enzyme that degrades the extracellular matrix, contributing to BBB permeability). In the in vivo mouse model, Kisspeptin-10 treatment resulted in significant improvements in cognitive function and reduced neuronal damage, reversing the detrimental effects of HIV-1 Tat exposure.