A concept describes the purpose, scope, and objectives of a potential funding opportunity. Approved concepts are usually developed into Requests for Applications (RFAs), in which funds are set aside by the Institute to stimulate a specific program of research. Concepts are being posted to give interested researchers additional time to plan for application submissions.
Please send questions regarding specific concepts to the program contact listed in the description. Please also note that to avoid any conflicting information, once a concept has been finalized as a published RFA (or similar funding announcement), it is deleted from this early notification, concept clearance list.
- HIV-Associated Neuropathic Pain and Opioid Interaction
- Pharmacogenomics of Immune Recovery in People Who Inject Drugs (PWID)
- Identification of Immune and CNS Biomarkers of HIV Infection and Substance Abuse Comorbidity
- Improving Implementation of Seek, Test, Treat & Retain among PWID in International Settings
- Pre-Exposure Prophylaxis for HIV Prevention and Treatment for Substance Using Populations
- Exploiting HIV/Host Genomic Information to Understand HIV Compartments in Substance Using Populations
With increased survival of HIV-infected patients due to antiretroviral therapy (ART) there is an increase in those living with neuropathic pain. Despite long-term ART, low levels of viral replication persists in CNS HIV reservoirs resulting in constant release of neurotoxic HIV proteins, including Tat and gp120. These toxic proteins have potential to contribute to neuropathic pain directly via inducing neuronal damage and indirectly via glia activation. In addition, HIV-infected opioid abusers appear to exhibit more severe neuropathy than HIV-infected non-drug users and repeated use of opioid analgesics promote chronic pain in HIV patients. The purpose of this RFA is to promote research investigating the underlying cellular, molecular, genetic, and epigenetic mechanisms whereby opioids including prescription drugs exacerbate HIV-associated neuropathic pain. Some of the proposed mechanisms are upregulation of TLR4, CXCR4, and CCR5 receptors and increased transfer of intestinal bacteria to the peripheral circulation. The ultimate goal is to obtain information for developing safe and effective treatments of neuropathic pain for HIV-infected patients exposed to opioids.
Vishnudutt Purohit - Program Officer, Integrative Neuroscience Branch/Division of Neuroscience and Behavior
Twenty percent of HIV infected individuals who successfully suppress plasma viremia below the limits of detection do not recover sufficient CD4+ T cell counts. The failure to recover normal CD4+T cells after anti-retroviral therapy is associated with intravenous drug use. Poor CD4+T cell recovery is associated with increased mortality and morbidity that has a genetic component. The goal of this funding opportunity is to identify genetic variants and epigenetic modifications affecting failure of recovery of CD4+T counts (<200) in PWID/HIV+ and PWID-/HIV whose viral load has been suppressed by ART for two years using existing resources or doing a prospective study. The resulting study will also provide information about gene by intravenous drug use interaction on recovery of CD4+ T cell count.
Dr. Jonathan D. Pollock - Branch Chief, Genetics, Epigenetics, and Developmental Neuroscience Branch/Division of Neuroscience and Behavior
Research Objectives: The FOA fosters biomarker research to advance clinical assessment of damages and functional reservation of host defense mechanism and comorbid complications at different phase of HIV-1 pathogenesis. Neuroimmunological profiling study is encouraged for comprehensive evaluation of blood and CSF soluble and cellular proteins and other molecules that change during HIV infection and accompanying inflammatory and neurodegenerative alterations. The study will enable identification of a set(s) of biomarkers that reflect the degree of damage and functional resilience ability of the defense system, and that will facilitate establishment of standards, and normal range of clinical lab tests that can detect early signs, and differentiate level of functional and structural deterioration of the compromised immune and neural system.
Background: HIV infection and chronic use of drugs of abuse (SUD) both change biological homeostasis and host defense mechanism. Current knowledge about the underlying inflammatory and degenerative process is largely based upon observations from small samples, suggesting altered signaling of a handful of pro-inflammatory and neurodegenerative molecules correlated with the diseases. The correlational data has limited clinical value, especially when information on molecules with anti-inflammatory or neuroprotective action is missing. A comparative assessment of blood and CSF samples will permit initial characterization and screen of molecular markers most representative of the compromised defense mechanism. The findings can then be validated by proof-of-concept studies to facilitate formation of a panel(s) of signatures that can be used for objective and quantitative assessment of disruptions in immune and neural system, and prediction of general immunity and functional resiliency of the patients.
Yu ‘Woody’ Lin, Ph.D. - Program Official, Integrative Neuroscience Branch/DNB
People who inject drugs (PWID) continue to have HIV incidence and prevalence above national averages in many places throughout the world. National responses to PWID often are weak and usually lag responses among other populations. Similarly, PWID engagement in HIV care generally lags behind other key populations as well as the larger population of people living with HIV. Even in some “general population epidemic” countries, HIV disparities in among PWID can limit the overall success of the UNAIDS 90-90-90 strategy. Seek, test, treat, and retain strategies need to be implemented in all key populations, including PWID in order to succeed. More service integration is needed in affected countries, including integration of HIV prevention and treatment for PWID and integration of drug use and HIV services, generally, along with attention to polysubstance use among PWID. This requires better models for program implementation and efforts to increase the implementation capacity of national HIV/AIDS programs among drug users.
This concept would support developing and testing implementation models that can be scaled-up in affected countries. Sustainable programs will need to align with national HIV/AIDS plans and provide models for large scale implementation, including QA/QC systems. This effort would include collaboration with national HIV/AIDS programs as well as major donors such as PEPFAR and Global Fund, which have platforms for reaching PWID and provide access to local epidemiology and services data. PEPFAR’s implementing partners include SAMHSA which provides specific substance use technical assistance in a number of countries. New donor programs include syringe services and drug treatment settings that can be leveraged to provide or actively link to additional HIV and substance use services. Some countries are developing new health financing systems that also can be leveraged to expand HIV prevention and treatment for PWID. In addition, projects would be encouraged to make use of existing NIH initiatives such as NIDA-funded researcher networks and IeDEA (NIH’s cohort of cohorts co-funded by NIDA) which provides clinical cohort platforms that can be leveraged for new research.
We plan to engage PEPFAR, Global Fund and SAMHSA, along with NIDA co-funded programs such as IeDEA as partners for these projects. Individual projects will be expected to leverage resources related to existing federal programs and align with national HIV/AIDS plans which generally have integration with US and international donor funding programs.
Dr. Richard Jenkins, Program Officer, Prevention Research Branch, Division of Epidemiology, Services and Prevention Research
Antiretroviral treatment (ART) used prophylactically in the form of pre-exposure prophylaxis (PreP; e.g., emtricitabine and tenofovir disoproxil fumarate [Truvada®]) is recommended for populations at high risk for HIV acquisition,, including individuals who have injected drugs in the past 6 months and have shared needles or works or been in drug treatment in the past 6 months. The seminal trial to date on the efficacy of PreP among injecting populations is the Bangkok Tenofovir Study, in which there were 17 HIV infections among the 1,204 participants taking tenofovir, compared with 33 infections among the 1,207 participants taking placebo (49% reduction in risk of HIV acquisition among those receiving tenofovir). The sample was recruited from methadone clinics and no data were reported on drug use or injection behavior, and no drug testing was performed (Choopanya K. et al. 2013). Consequently, the actual efficacy of PreP for active injectors, adherent methadone users or even non-injectors who actively use opiates and other drugs is unknown.
NIDA has funded surprisingly little research on the several key question related to PreP use among substance using populations The primary goal of this RFA is to examine the role of PreP in substance use trajectories and or treatments, including:
- To what degree do substance use or HIV providers recommend or adopt PreP for substance using patients at risk for HIV (e.g., injection drug use)?
- To what degree does substance use affect access and adherence to PreP?
- How does drug use interact with PrEP efficacy, including injection as well as polydrug use with substances that independently affect immune function?
- Where does PreP fit within a comprehensive program for prevention of HIV acquisition?
This concept is squarely in line with high overarching HIV/AIDs priorities (NOT-15-137):
- Reducing Incidence of HIV/AIDS, including: developing and testing pre-exposure prophylaxis candidates and methods of delivery, especially those that mitigate adherence issues; and developing, testing, and implementing strategies to improve HIV testing and entry into prevention services.
- Next generation of HIV therapies with better safety and ease of use including: developing and testing HIV treatments that are less toxic, longer acting, have fewer side effects and complications, and easier to take and adhere to than current regimens. Additionally, implementation research to ensure initiation of treatment as soon as diagnosis has been made, retention and engagement in these services, and achievement and maintenance of optimal prevention and treatment responses.
Shoshana Y. Kahana, Ph.D., Health Scientist Administrator, Services Research Branch, Division of Epidemiology, Services and Prevention Research
Exploiting HIV/Host Genomic Information to Understand HIV Compartments in Substance Using Populations
Upon cellular infection, the approximately 10,000 nucleotide HIV RNA genome is copied into complementary DNA (cDNA) by an error prone reverse transcriptase. The other strand of the cDNA is then synthesized and the double-stranded HIV genomic DNA is integrated into the host cell genome where it either remains dormant or is transcribed into new HIV RNA genomes. During this process, a reverse transcription error or mutation in an HIV DNA genome that is latently integrated into the host genome is “frozen in time.” This DNA sequence information can be used to investigate HIV compartment formation and latent reactivation.
Additionally, chromatin architecture assays indicate that the HIV DNA genome tends to integrate into host chromatin near the nuclear pore. However, there is much that we do not understand about HIV integration sites and how they may differ between types of HIV-infectable cells.
This initiative will support exploratory and hypothesis-driven research projects that:
- exploit integrated HIV genomic sequences to better understand how founder HIV seeds cellular compartments over time in individuals with and without substance use disorders (SUDs), or
- explore how substance use and/or suboptimal antiretroviral therapy adherence impacts reactivation of latent HIV in cellular compartments, or
- exploit epigenomic or chromatin architecture assays to investigate factors that influence the sites of HIV integration within the host genome in different cellular compartments and how substance use influences these factors.
These research areas could be explored using fresh accessible tissues or post-mortem tissues including brain. Ultimately this research will yield foundational knowledge that will help inform the development of a future HIV cure for patients with SUDs.
John Satterlee, Ph.D., DNB Coordinator for Trans-NIH Programs and Activities, Division of Neuroscience and Behavior