Immune dysregulation in HIV-infected adults with substance abuse and the impact of addiction therapy

Research project

Description

? DESCRIPTION (provided by applicant): Challenges in establishing adherence to antiretroviral therapy and other medical interventions contribute to poor outcomes observed among HIV-infected individuals with substance abuse. However, it is also clear that drugs of abuse such as alcohol and opioids have direct interactions with the immune system that accelerate HIV pathogenesis and may also independently contribute to chronic immune dysregulation and activation. Understanding how drugs of abuse, and the medications utilized to manage substance abuse, impact immune function and inflammation is particularly relevant as chronic immune activation is strongly correlated with progression to AIDS, as well as non-HIV related morbidity and mortality. The immunologic consequences, and underlying biologic mechanisms, of alcohol and opioid agonists remain controversial. Recent evidence suggests that interactions between either ethanol or exogenous opioids (such as morphine), and Toll-like receptors (TLR) results in exaggerated neuroinflammatory responses to TLR- ligands. TLR are pattern recognition receptors expressed by adaptive and innate components of the immune system that alert to danger signals. TLR-mediated immune activation by drugs of abuse may lead to chronic and dysregulated immune activation, immune exhaustion, and thereby predispose individuals to consequences of chronic systemic inflammation. Our central hypothesis is that chronic opioid and alcohol use in HIV-infected individuals exaggerates immune dysregulation and chronic inflammation due to altered peripheral TLR responses, and that this dysregulation is reversible through treatment with the opioid antagonist naltrexone. In conjunction with the NIDA CTN-0055 CHOICES pilot study, we have an opportunity to investigate immune activation and function in HIV-infected individuals with opioid and/or alcohol dependency. Notably, CHOICES participants are randomized to receive addiction treatment with a long acting opioid-antagonist, extended- release naltrexone (XR-NTX) versus treatment as usual (TAU) without the use of opioid antagonists, and followed longitudionally. Therefore, we will be able to compare the effects of different treatment strategies for addiction on a variety of immune activation parameters among HIV-infected individuals. Moreover, our inclusion of a comparison group will determine if HIV-infected individuals with substance abuse have significant alterations in immune activation profiles and altered measures of TLR function and expression, as compared to HIV-infected individuals without substance dependency.
StatusActive
Effective start/end date4/1/163/31/18

Funding

  • National Institutes of Health: $154,000.00

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Substance-Related Disorders
HIV
Therapeutics
Toll-Like Receptors
Opioid Analgesics
Alcohols
Narcotic Antagonists
Street Drugs
Inflammation
Naltrexone
Immune System
Pattern Recognition Receptors
Morphine
Acquired Immunodeficiency Syndrome
Ethanol
Ligands
Morbidity
Mortality