Funding Opportunity: Nicotinic Immune Modulation in the Presence of HIV-1 Infection (R01)

The Centers for Disease Control and Prevention reports that more than twice as many HIV+ patients smoke relative to the general population. Tobacco smokers with HIV+ infection experience increased HIV pathogenesis and disease progression, and have more HIV-associated infections and other health conditions. Smokers are also less likely to adhere to a HIV treatment plan presumably due to cognitive deterioration and, consequently, have poorer HIV treatment outcomes than non-smokers. This suggests that smoking may influence the rate of HIV disease progression and the development of behavioral and cognitive complications.

HIV-1 infection elicits a pro-inflammatory immune response that contributes to the development of HIV-induced pathologies, and behavioral and cognitive deficits. Nicotine regulates immune system function and the expression of pro- and anti-inflammatory factors. Nicotinic acetylcholine receptors (nAChRs) are expressed on central and peripheral immune cells. Acetylcholine activation of these receptors has been shown to decrease T cell proliferation and activation, increase the production of anti-inflammatory cytokines, and decrease the expression of pro-inflammatory cytokines. Most peripheral immune cells including T cells, and central glial cells, express a variety of nAChR subunits (a2 – a7, a9, a10 and ß2–ß4) that associate in multiple conformations to produce a variety of nAChRs with different functional properties. The protective actions of nicotine, such as preserving the functional integrity of biological systems or promoting restoration and recovery from damage, are evident by selective activation of nAChRs containing a7 or a4ß2 subunits.  Activation of these receptors has been shown to reduce inflammatory responses, enhance cognition and attenuate depression, maintain or improve neuroplasticity, induce neurotrophic modulation, stimulate anti-apoptotic actions, reduce protein aggregation, and improve blood brain barrier function.

The above discussion suggests that nicotine might be protective or counteract the detrimental immune response induced by HIV-1 infection. If nicotinic signaling through nAChRs positively modulates immune cell signaling, then manipulating endogenous nicotinic signaling may improve immune function and glial plasticity and potentially mitigate HIV-associated deterioration.  However, it has been shown that nAChRs are downregulated and desensitized by prolonged exposure to nicotine. This suggests that chronic smoking and long-term exposure to nicotine may attenuate nicotine’s ability to mediate its protective action through immune system function. Likewise, HIV-1 infection may disrupt or override the protective ability of nicotinic immune modulation due to perturbed homeostasis. HIV-1 infection impair both innate and adaptive immune responses and represent a dynamic alteration of both local and systemic pro- and anti-inflammatory molecules.  An in-depth analysis of the alterations in nicotinic immune modulation due to chronic smoking and HIV-1 infection as it affects HIV pathogenesis and CNS complications may help to elucidate the status of host homeostatic disruption and potential functional recovery mediated by nicotine and nAChR activation.

Therefore, a comprehensive assessment of inflammation, relative to changes in nicotinic immune-modulation, and its association with features such as status of immune function, CNS complications and/or other comorbid conditions, and functional resiliency, during different stages of the HIV progression, and among different patient populations (e.g., smoker vs. HIV+ smoker vs. HIV+ non-smoker, with or without neurological/cognitive disorders) may help us better understand and treat HIV pathology.

The FOA encourages the submission of research project applications to determine nicotine’s modulatory effects on peripheral and central immune system functions in the presence of HIV-1 infection.  Specifically, NIDA is particularly interested in projects exploring the ability of nicotine to produce anti-inflammatory and protective effects, and the translational potential of the new knowledge in attenuating HIV-induced pathologies and HIV-associated CNS complications such as neurological/cognitive disorders including premature aging.

Responsive studies to this FOA will identify functional, molecular, or behavioral indicators and circuit features that reflect a causal, rather than correlational, relationship of the properties of endogenous cholinergic immune modulation to the health consequences of HIV pathogenesis and CNS complications in HIV-infected persons who smoke tobacco. Interdisciplinary approaches are strongly encouraged to promote a comprehensive evaluation of the immune-brain relationship with attention to host immune status, affective stability, neurocognitive strength and quality of life functionality.

Proposed projects MUST include the following:

• ALL proposed aims must investigate a high priority research area, in the context of HIV infection/AIDS, as defined in NOT-OD-15-137, and
• A major theme of all applications must address the interaction of chronic exposure to tobacco smoking/nicotine and HIV pathogenesis, and
• Application that lacks of these two criteria will be considered non-responsive and will not be discussed.

Other application considerations:

Applicants are encouraged to collect immunomic profiles (defined as immune-regulatory molecules, neurotrophic factors, and transforming growth factors) in the study, with attention to both anti- and pro-inflammatory factors, rather than focusing on responses mediated by individual immune factors since it is expected that the consequences of immune responses are mediated through the integration of actions due to multiple factors.

Research projects are strongly encouraged to focus on cognitive and behavioral consequences of HIV-1 infection, such as cognitive deficits and chronic sickness/fatigue syndromes.

Variables selected for analysis should be justified based upon well documented relevance to HIV-induced deteriorations, such as the relevance of adapted tests for attention or memory assessment to HIV-associated pathogenesis.

For human studies, stratification of research subjects should be justified.

For animal studies, applicants are encouraged to propose studies that employ behavioral models of smoking or nicotine exposure.

Applicants with interest in health risks of continued smoking, or smoking cessation in HIV+ smokers, are encouraged to consider applying through FOA PAR-14-231 (R33).

Responsive scientific themes may include, but are not limited to, the following examples and types of questions regarding nAChR-mediated immune modulation in relation to the homeostatic perturbation at different stages of HIV infection and among different patient populations

1. Determine the effects of HIV-mediated inflammation and/or the expression of viral proteins on nAChR subunit composition and function in immune and glial cells.

2. Determine the effects of HIV-1 infection on the ability of nicotine to induce nAChR-mediated immune system responses, such as cytokine and chemokine expression, from immune and glial cells.

3. Determine how the nAChR activation results in the preservation or restoration of biological function, cognition and behavior.  Does HIV-mediated inflammation affect nAChR activation and prevent the ability of nicotine to reverse HIV-produced immune system dysfunction?  Conversely, how the nicotinic immune modulation was altered as a consequence of HIV-produced host immune system dysfunction in HIV-infected smokers with or without cART (antiretroviral combination therapy), or in appropriate animal or in vitro models?

4. Characterize the effects of the interactions between nicotine and nAChR-mediated immune activation in the presence or absence of chronic exposure to tobacco smoking and nicotine, and HIV-mediated inflammation in the presence or absence of cART, on neurobiological function and processes such as glia-neuron communication, neural plasticity, cognitive strength or mental flexibility.

5. Compare and contrast the effects of chronic smoking and nicotine exposure and HIV-1 infection on innate and adaptive immune system responses. Additionally, determine whether chronic smoking and nicotine exposure alters susceptibility to HIV infection?

6. Determine the effects of acute and long-term cART treatment on HIV-mediated immune responses, including changes in immune factor expression, and on nAChR receptor structure and function on immune cells and glial cells. How does the course of cART treatment affect HIV- and nicotine-mediated immune responses?

7. Determine the degree to which cART treatment results in a reduction of specific HIV-induced neural and cognitive consequences. Is functional improvement affected by immune system function, the length of cART therapy, or the degree of exposure to tobacco smoking or nicotine?

8. Characterize the similarities and differences between peripheral and CNS immune cell responses and consequent effects of nicotinic immune modulation during different stages of HIV infection (e.g. successful HIV suppression by cART), among smokers and non-smokers, and in the presence and absence of cART.

9. Determine how systemic inflammation, i.e. immune factor expression (immunomic profiles, defined as immune-regulatory molecules, neurotrophic factors, and transforming growth factors), changes over time with chronic viral and nicotine-mediated immune system activation, and the expression and progression of HIV-induced complications in HIV-infected smokers on cART.

10. Employ systems biology approaches towards understanding integrated HIV- and nicotine-mediated anti- and pro-inflammatory immune signaling. Determine the immune expression profiles of HIV-infected individuals, including comparisons of HIV- and HIV+ individuals, chronic smokers and non-smokers, and HIV+ individuals with and without anti-retroviral therapy. Additionally, determine whether immunomic profiles can serve as predictors or signatures of HIV-induced complications in HIV+ smokers, such as host functional integrity, disease progression, degree of CNS complications, status of immune preservation, and restorative capacity from HIV-induced complications, and effectiveness of treatment or prognosis of functional recovery.

11. Explore pharmacological and other approaches that target nAChR and nicotine-mediated immune system activation and the ability to enhance nicotinic regulatory capacity to improve immune plasticity and immune strength, and determine whether enhanced nicotine-mediated immune regulation can mitigate HIV-associated inflammation and the consequences of HIV-1 infection.

12. Determine the translational potential and generalizability of manipulating the nicotine-mediated inflammatory response towards diagnosis and treatment approaches and recovery from HIV-induced complications.

See Section VIII. Other Information for award authorities and regulations.