Plasma dickkopf-related protein 1, an antagonist of the Wnt pathway, is associated with HIV-associated neurocognitive impairment

Abstract

Objective DKK1 is a soluble antagonist of the Wnt pathway. It binds to and sequesters LRP5/6 away from Wnts. Because the Wnt pathway regulates synaptic transmission and plasticity, we hypothesized that increased DKK1 would increase the risk for neurocognitive impairment (NCI) in HIV+ individuals. We evaluated here the relationship between plasma DKK1 and global NCI. Methods Plasma samples and data from 41 HIV+ and 42 HIV− adults were obtained from the University of California, San Diego. Concentrations of DKK1 and a comparator protein, MCP-1, were quantified in plasma by immunoassay. All subjects completed a standardized comprehensive neuropsychological test battery and their performance was summarized using the global deficit score (GDS) method. Results A higher DKK1 level was associated with NCI among HIV+ participants (d=0.63, p=0.05), particularly among the 26 participants whose plasma HIV RNA level was suppressed (d=0.74, p=0.08). DKK1 level was not associated with NCI among HIV− participants (p=0.98). MCP-1 was not associated with NCI in either group. In HIV+ adults with suppressed plasma HIV RNA, a receiver-operator characteristic curve identified that a DKK1 level of at least 735 pg/ml had a positive predictive value of 83.3% for a diagnosis of NCI. This association did not weaken after accounting for the effect of AIDS, nadir CD4+ T-cell count, addictive drug use, or demographic characteristics. Conclusion DKK1 is a specific biomarker for NCI in HIV+ adults, implicating the Wnt pathway in HIV neuropathogenesis.

HIV-Associated Neurocognitive Impairment in the Modern ART Era: Are We Close to Discovering Reliable Biomarkers in the Setting of Virological Suppression?

“…The Dickkopf-related protein 1 (DKK1) is a secreted soluble antagonist of the Wnt pathway that induces the rapid disassembly of synapses in mature neurons, and it mediates synaptic loss induced by Aβ (Purro et al, 2012). In HIV-infected subjects, DKK1 levels did differ with NCI (mean 813 pg/ml vs. 549 pg/ml, p < 0.05), particularly in PWH taking ART with HIV RNA levels ≤50 c/ml (Yu et al, 2017). Even if studies are still lacking in HIV, Wnt pathway regulates synaptic transmission and plasticity, and its study could provide a new understanding of some neuropathological processes in the course of HAND.…”

Exploration of the involvement of LncRNA in HIV-associated encephalitis using bioinformatics

“…The activation of the Wnt signaling pathway could promote the occurrence of autoimMune encephalitis ( Schneider et al, 2016 ), and the Wnt signaling pathway was involved in the immunity and tolerance of dendritic cells ( Swafford & Manicassamy, 2015 ). Moreover, plasma Dickkopf-related protein 1, the antagonist of the Wnt signaling pathway, was associated with HIV-related cognitive deficits ( Yu et al, 2017 ). Therefore, KEGG analysis showed that most of the significant clustering pathways were related with the function of the nervous system.…”

Peer Review #1 of "Exploration of the involvement of LncRNA in HIV-associated encephalitis using bioinformatics (v0.1)"

“…Moreover, plasma Dickkopf-related protein 1, the antagonist of the Wnt signaling pathway, was associated with HIV-related cognitive deficits (Yu et al 2017). Therefore, KEGG analysis showed that most of the significant clustering pathways were related with the function of the nervous system.…”