Abstract
HIV-Associated Dementia (HAD) is a significant comorbidity that many HIV-patients face. Our study utilized QIAGEN Ingenuity Pathway Analysis (IPA) to identify and analyze molecular profiles and pathways underlying nicotine’s impact on HAD pathology. The Qiagen Knowledge Base (QKB) defines HAD as “Dementia associated with acquired immunodeficiency syndrome (disorder).” Although much remains unknown about HAD pathology, the curated research findings from the QKB shows 5 upregulated molecules that are associated with HAD + : CCL2 (Chemokine (C–C motif) ligand 2), L-glutamic acid, GLS (Glutaminase), POLG (DNA polymerase subunit gamma), and POLB (DNA polymerase subunit beta). The current study focused on these 5 HAD pathology molecules as the phenotype of interest. The Pathway Explorer tool of IPA was used to connect nicotine-associated molecules with the 5 HAD associated molecules (HAD pathology molecules) by connecting 29 overlapping molecules (including transcription regulators, cytokines, kinases, and other enzymes/proteins). The Molecule-Activity-Predictor (MAP) tool predicted nicotine-induced activation of the HAD pathology molecules indicating the exacerbation of HAD. However, alternative pathways with more holistic representations of molecular relationships revealed the potential of nicotine as a neuroprotective treatment. It was found that concurrent with nicotine treatment the individual inactivation of several of the intermediary molecules in the holistic pathways caused the downregulation of the HAD pathology molecules. These findings reveal that nicotine may have therapeutic properties for HAD when given alongside specific inhibitory drugs for one or more of the identified intermediary molecules.
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Abbreviations
- AIDS:
-
Acquired Immunodeficiency Syndrome
- ADC:
-
AIDS-dementia complex
- BBB:
-
Blood brain barrier
- CCL2:
-
Chemokine (C-C motif) ligand 2
- DCs:
-
Dendritic cells
- GLS:
-
Glutaminase
- HAART:
-
Highly active antiretroviral therapy
- HAD:
-
HIV-Associated Dementia
- HANDs:
-
HIV-Associated neurological disorders
- HIV:
-
Human Immunodeficiency Virus
- IPA:
-
Ingenuity Pathway Analysis
- IL-1β:
-
Interleukin-1β
- ICAM-1:
-
Intercellular adhesion molecule‐1
- MAP:
-
Molecule-Activity-Predictor
- MCP-1:
-
Monocyte chemoattractant protein‐1
- POLG:
-
DNA polymerase subunit gamma
- POLB:
-
DNA polymerase subunit beta
- QKB:
-
Qiagen Knowledge Base
- Tat:
-
Transcriptional transactivator
- TNF:
-
Tumor Necrosis Factor
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Acknowledgements
The authors thank Dr. Eric Seiser for initial use of QIAGEN Knowledge Base and QIAGEN Ingenuity Pathway Analysis tools.
Funding
This study was partially supported by National Institute of Health grants DA43448 and DA046258 to SLC.
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Krishnan, V., Vigorito, M., Kota, N.K. et al. Meta-Analysis on Nicotine's Modulation of HIV-Associated Dementia. J Neuroimmune Pharmacol 17, 487–502 (2022). https://doi.org/10.1007/s11481-021-10027-2
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DOI: https://doi.org/10.1007/s11481-021-10027-2