Chronic and sustained neuroinflammation is a hallmark feature underlying HIV-associated neurocognitive disorders (HAND). Factors contributing to this inflammation have been suggested to involve low-level HIV replication/HIV proteins and/or toxicity of cART istelf. It is well recognized that drug abuse, specifically opiate abuse, is a common comorbidity among individuals with HAND. Intriguingly, opiates have also been shown to exacerbate neuroinflammation either through direct effect on immune cells such as microglia and/or by decreasing the effectiveness of cART against HIV replication. It can thus be envisioned that within the CNS, combinations of HIV proteins, abused drugs and cART create a toxic milieu promoting exacerbated neuroinflammation. The detailed molecular pathways underlying this phenomenon however, remain elusive. Our preliminary studies using each of these factors demonstrate that: 1) HIV TAT can increase microglial activation via the NLRP3 inflammasome signaling; 2) Opiates such as morphine activate microglia via dysregulated autophagy pathway & 3) Combination of clinically used antiretrovrials (TFV, FTC, DTG) increase ER stress activity of microglia leading to their activation. Furthermore, we also demonstrated that combined exposure of TAT, morphine & cART in microglia resulted in exacerbated production of the pro- inflammatory mediator IL-6 (compared with cells treated with individual factor) and a concomitant disruption of the mitochondrial membrane in vitro. We thus hypothesize that combinations of HIV TAT, morphine & cART can activate microglia via the inflammasome, autophagy and ER stress pathways. Using in vitro and in vivo (HIV Tg rats) approaches we will test the hypothesis via two specific aims - SA1: Investigate the molecular mechanism(s) underlying TAT, morphine & ARVs (3 drug regimen) mediated activation of microglia in vitro; and SA2: To determine the mechanisms underlying Tat, morphine and cART-mediated neuroinflammation in vivo in a rodent model of HAND. Two experienced PIs (Drs. Guo & Buch) will co-lead this project to accomplish the proposed goals. This proposal is in response to NIDA RFA-DA-17-013 on ?Mechanisms of Immune Activation and Inflammation: HIV Infection, ART, and Drugs of Abuse (R01)?.

Public Health Relevance

HIV-infected individuals on antiretrovirals (ARV) have underlying neuroinflammation leading to increased rates of cognitive complications. Most of these individuals also have the issue of opiate addiction leading to further increase in inflammation and cognitive decline. Understanding how HIV proteins, ARVs & opiates converge to cause exacerbated neuroinflammation could have ramifications for future development of therapeutic interventions for treatment of neuroinflammation in HIV-infected with morphine in the presence of cART.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA044586-02
Application #
9511767
Study Section
Special Emphasis Panel (ZDA1)
Program Officer
Tsai, Shang-Yi Anne
Project Start
2017-07-01
Project End
2022-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Guo, Ming-Lei; Kook, Yeon Hee; Shannon, Callen E et al. (2018) Notch3/VEGF-A axis is involved in TAT-mediated proliferation of pulmonary artery smooth muscle cells: Implications for HIV-associated PAH. Cell Death Discov 4:22
Thangaraj, Annadurai; Periyasamy, Palsamy; Liao, Ke et al. (2018) HIV-1 TAT-mediated microglial activation: role of mitochondrial dysfunction and defective mitophagy. Autophagy 14:1596-1619
Sil, Susmita; Niu, Fang; Tom, Eric et al. (2018) Cocaine Mediated Neuroinflammation: Role of Dysregulated Autophagy in Pericytes. Mol Neurobiol :