Profile of neuronal exosomes in HIV cognitive impairment exposes sex differences

Objective: To use plasma neuron-derived exosomes (NDEs) to detect proteins that diagnose HIV-associated neurocognitive disorders (HAND). To compare NDE cargo from HAND with Alzheimer’s disease. Design: Eighty plasma samples were assayed including men (n¼29) and women
(n¼51) with and without HAND.

Methods: Plasma NDEs were isolated by immunoadsorption with neuron specific L1 cell adhesion molecule antibody. NDE proteins were quantified by ELISA and proximity extension assays for 184 targets.

Results: Neuronal enrichment of NDE was confirmed with elevated synaptophysin and normalized to the exosomal marker, apoptosis-linked gene-2-interacting protein X (ALIX). NDE from men and women had significant divergent results. High mobility group box 1 and neurofilament light were significantly increased in NDE from cognitively impaired men and were unchanged in women. NDE from HIVþ men had decreased p-T181-tau, a marker increased in Alzheimer’s disease, compared with no difference in women. NDE amyloid beta was not increased in cognitive impairment. Proximity extension assays analysis showed 25 proteins were differentially expressed in HIV infection alone. Seven proteins identified asymptomatic and mild cognitive impairment in HIVþ women. NDE from women had significantly decreased cathepsin S, total tau, neuronal cell adhesion molecule and contactin 5 in mild impairment. Twelve proteins were increased in NDE from cognitively impaired men, including carboxypeptidase M, cadherin 3, colony stimulating factor 2 receptor alpha subunit and mesencephalic astrocyte-derived neurotropic factor.

Conclusion: NDE proteins differ in HIV infection alone and cognitive impairment between men and women suggesting mechanistic sex differences associated with HAND. Several NDE targets are different from that reported for Alzheimer’s disease.