Sex related differences in cognitive deficits: Disrupted Arc/Arg3.1 signaling in an HIV model

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Combined and highly active antiretroviral therapies (cART) have made HIV a chronic condition.
• Despite cART, approximately half of people living with HIV (PLWH) experience neurocognitive disorders.
• Sex-specific effects on cognition in PLWH are understudied, despite the increasing proportion of females living with HIV.

Purpose of the Study:

• To investigate sex-specific effects of HIV-1 Tat protein on cognitive behaviors and memory-related biomarkers.
• To examine the role of activity-regulated cytoskeleton-associated protein (Arc) in HIV-associated cognitive changes.

Main Methods:

• Utilized a transgenic mouse model expressing HIV-1 Tat in the central nervous system (CNS).
• Assessed cognitive behaviors including spatial learning, memory, object recognition, and fear memory.
• Measured hippocampal expression of Arc, amyloid-beta (Aβ) monomers/oligomers, and phosphorylated CREB (pCREB).
• Investigated Tat exposure effects on Arc expression in cultured human neurons.

Main Results:

• HIV-1 Tat-expressing males showed deficits in spatial learning/memory and object recognition.
• Tat-expressing females exhibited enhanced fear memory.
• Hippocampal Arc induction after foot shock occurred in Tat+ females but not Tat+ males.
• Arc, Aβ, and pCREB levels were altered in a sex-specific manner.
• CREB activity was reduced solely in Tat+ males.
• In vitro Tat exposure decreased Arc expression in human neurons.

Conclusions:

• HIV-1 Tat protein influences cognitive function and related molecular pathways in a sex-dependent manner.
• Differential effects of Tat on CREB/Arc signaling may underlie observed sex differences in cognitive outcomes in PLWH.
• These findings highlight the importance of considering sex as a biological variable in HIV-associated neurocognitive research.