June 2017 DAIDS Council-Approved Concepts

Concepts represent early planning stages for program announcements, requests for applications, or solicitations for Council's input. If NIAID publishes an initiative from one of these concepts, we link to it below. To find initiatives, go to Opportunities & Announcements.

NB: Council approval does not guarantee that a concept will become an initiative.

Table of Contents

Targeted In Vivo Delivery of Gene Therapeutics for HIV Cure

Request for Applications—proposed FY 2019 initiative

Contact: Betty Poon

Objective: This initiative will advance strategies to deliver anti-HIV gene therapies to specific target cells in vivo. It is hoped that these studies will advance specific anti-HIV gene therapy approaches toward clinical applications.

Description: This initiative will support developing technologies to deliver anti-HIV gene therapy payloads in vivo to specific cells or sites. The challenges that need to be overcome with in vivo gene therapeutic strategies are 1) inefficient delivery to specific target cells and sites, 2) selective regulation of genetic payload expression to maximize on-target efficacy and minimize off-target effects, and 3) the potential immunogenicity of delivery vectors.

Some examples of underexploited delivery technology include but are not limited to:

  • Incorporation of novel cell-specific envelope proteins or ligands into viral or non-viral vectors
  • Vector engineering for cell-type specificity including target cell transduction and expression, increased in vivo stability, and reduced immunogenicity
  • Improved efficiency of nuclear transport and uptake of genetic payloads

Applications will include:

  • Gene therapeutic payload approach(es) with supporting data
  • In vivo animal studies well integrated into the research plan during the award period
  • In vivo analytical studies to inform the biological plausibility of the approach, e.g., analysis of bioavailability, tissue distribution, expression, and stability

Exclusions:

  • Ex vivo studies that do not include an in vivo targeting delivery component
  • Discovery or development of new gene therapeutic payloads

Next Generation Biologics for Sustained HIV Remission

Request for Applications—proposed FY 2019 initiative

Contact: Brigitte Sanders

Objective: The scientific objective of this opportunity is to develop next-generation, truly innovative biologics that can achieve post-treatment controller status in HIV-infected individuals. The recent finding that treatment of SIV-infected monkeys with an anti-α4β7antibody regimen led to a functional cure sparks the notion that other biologics could also induce prolonged HIV control within a host.

The goal of this initiative is to expand the development and testing of additional biologics with the potential to induce viral remission. Examples of next-generation biologics that are being developed and evaluated in other disease settings include: stapled peptides, antibody-drug conjugates, tri-specific antibodies, hexabodies, minibodies, xenonucleic assays, mRNA platforms for antibodies and proteins, and biobetters.

This initiative is directed towards a high-priority area for the Division of AIDS and the Office of AIDS Research. It is designed to encourage investigators from other fields to apply their ideas and technologies to HIV therapeutic research. For this purpose, cross-disciplinary partnerships between leaders in the field of immunotherapy and HIV from the academic, non-for-profit, and private sector are encouraged.

Description: This new initiative will support discovery and development of next-generation biologics to prevent HIV rebound. Applications will be structured with milestones to demonstrate feasibility of the proposed concept within two years (R61 phase). If the milestones have been achieved, the grant is eligible to transition to the R33 phase.

The prospective applicants are required to describe how their proposed biologic could lead to HIV remission. Ideally, the candidate biologic would not have previously been exploited in the HIV field and would leverage the newest immuno-pharmacological technologies and platforms. Successful biologics approaches studied under this initiative should be poised to transition into clinical programs as soon as possible.

Examples of responsive research activities include but are not limited to:

1. Design innovative biologics that interact with a target or regulate a pathway involved in HIV control.

  • The proposed immunotherapeutics can target viral and/or host proteins and can be either a stand-along biologic or a biologic linked to a payload.
  • Computational tools for designing and/or optimizing biologics should be considered to reduce development time.

2. Optimize the drug attributes of existing biologics to mediate HIV control by modifying their molecular constitution. For example:

  • Explore modified or alternative scaffolds.
  • Optimize post-translational modifications.

3. Determine efficacy in appropriate in vitro and/or animal models.

  • Develop analytical assays to determine pharmacokinetics and pharmacodynamics.

4. Evaluate next-generation biologics for toxicity.

  • Characterize off-target effects such as immunogenicity, immunotoxicity, immune complex formation, and end-organ toxicity.

NIH AIDS Reagent Program

Request for Proposals—proposed FY 2019 initiative

Contact: Kishan Patel

Objective: The objective of the NIH AIDS Reagent Program (ARP) is to facilitate HIV/AIDS research by providing access to standardized state-of-the-art reagents, technology, and other research resources to investigators around the world.

Description: This initiative will provide continued support for a contract to acquire state-of-the-art HIV/AIDS-related research and reference reagents; produce reagents, standardized panels, and protocols; and provide these reagents at minimal cost to qualified investigators throughout the world. Additionally, the ARP collects information about AIDS-related reagents and standards and disseminates this information to the research community, enhances technology transfer and publication of methods, and facilitates the availability of reagents through proactive communication with biotechnology and pharmaceutical companies.

HIV Drug Resistance: Genotype-Phenotype-Outcome Correlations

Request for Applications—proposed FY 2019 initiative

Contact: Keith Crawford

Objective: The objectives of this initiative are to provide data to better evaluate correlations between HIV drug resistance genotype, in vitro phenotype of the virus (i.e., drug susceptibility), and virologic outcome (i.e., virologic success or failure). Applications are sought in three specific areas:

  1. To better elucidate the role of minority variants in the development of resistance to antiretroviral drugs, and the effect of minor variants on virologic outcomes in both B and non-B subtypes. Standard genotypic resistance tests use Sanger sequencing to identify drug resistance mutations but can only detect mutations present at greater that 15 percent frequency of an individual’s quasispecies. Some studies suggest that mutations present at 1 percent or less may result in clinical treatment failure.
  2. To understand genotype/phenotype/outcome correlations in non-B subtypes. Non-B subtypes may have naturally-occurring polymorphisms that confer resistance to certain antiretrovirals. Resistance mutations may also have different effects (differences in fold-sensitivity to a drug) across subtypes. Some subtypes appear to display intrinsically reduced susceptibility to certain antiretroviral drugs, increasing the risk of failure.
  3. To better understand why some nucleoside reverse transcriptase inhibitors maintain activity and help prevent virologic failure in protease inhibitor-based regimens, in the presence of drug resistance mutations.

Description: Projects that will be supported include:

  • Studies focused on determining the biological basis for treatment success in settings where resistance is predicted by genotypic drug resistance results.
  • Studies focused on determining the biological basis for treatment failure in the setting where resistance is not predicted by standard genotypic testing and adherence is thought to be optimal.
  • Studies of genotype/phenotype/clinical outcome correlations across various clades/subtypes (including in vitro studies utilizing clinical samples) and different agents and combinations of agents.
  • Studies of the contribution of minor variants to drug susceptibility and virologic outcome and the point at which minor variants become clinically relevant.

For the above types of studies, investigators are encouraged to test in vitro susceptibility of viruses with combinations of mutations found in clinical specimens and to test not only in the presence of single drugs, but also with relevant combinations of antiretroviral drugs.

This initiative will not support:

  • Clinical trials, although the use of samples from prior clinical trials is encouraged.
  • Development of new cohorts but use of samples from established cohorts is permitted.
  • Surveys of resistance, although samples from surveys could be used in some studies.
  • Studies primarily focused on adherence.
  • Studies of HIV resistance to neutralizing antibodies or other biologicals.
  • Cost analysis studies.

NIAID Virology Quality Assurance (VQA) Program

Request for Proposals—proposed FY 2019 initiative

Contact: Rosemary Gomes

Objective: Provide a laboratory quality assurance program that includes proficiency testing and control reagents and standards for existing and newly developed virologic assays used by laboratories supporting DAIDS clinical trial networks, NIAID Study Groups, and collaborating domestic and international investigators. The program largely supports HIV virology activities but permits addition of other viral assays through the use of options.

Facilitate developing, standardizing, and validating virologic assay methodologies and their implementation in therapeutic, prevention, vaccine, epidemiological, and preclinical investigations.

Provide data management and statistical analysis to assess assay parameters including accuracy, precision, sensitivity, specificity, and linearity.

Provide options to increase services and/or laboratories to be supported by the contract.

Description: The Virology Quality Assurance contract supports a range of activities which include:

  • Providing a laboratory quality assurance program for virologic assays used to support NIAID clinical investigations. Specimens and biological samples may include whole blood, plasma, CSF, urine, tissue, and fresh and frozen samples.
  • Providing standardized reagents and proficiency testing panels for HIV RNA quantitation, qualitative HIV TNA detection, and HIV genotypic drug resistance.
  • Validating and providing proficiency panels, if necessary, for commercial and in-house assays for HIV-1, HIV-2, and additional HIV co-infections (HCV, HBV, CMV, HSV, KSHV, and HPV).
  • Standardizing and validating new virologic assays, including assays related to common infectious co-morbidities of HIV and assays measuring HIV reservoirs in cure research and point-of-care (POC) virologic assays.
  • Evaluating, standardizing, and validating new virologic assays for antiretroviral drug resistance.
  • Providing data management and statistical analysis to assess reproducibility and variability of assays.
  • If necessary, enabling expansion of the program (through contract options) to provide support to additional labs and to support development and quality assurance of assays and methods related to emerging viral pathogens. This capacity provides potential to serve other NIAID divisions.

Options will also be included to support late stage assay development and validation, as well as testing of samples from NIAID-sponsored clinical trials, in a CLIA-certified laboratory.

Halting TB Transmission in HIV-Endemic Settings

Request for Applications—proposed FY 2019 initiative

Contact: Sudha Srinivasan

Objective: The objectives of this request for applications are to promote research toward:

  1. Understanding of the critical drivers of tuberculosis (TB) transmission at the individual level and expanded to members of the Transmitter-Recipient Cluster Chains (TRCC) in HIV-infected populations.
  2. Potential interventions to prevent TB transmission underpinned by an increased understanding of the underlying biologic mechanisms.
  3. Understanding of biomedical, environmental, and population-based drivers of Mycobacterium tuberculosis (Mtb) transmission in HIV endemic settings.

Description: Unacceptable levels of M. tuberculosis transmission are noted in high-burden settings and a renewed focus on reducing person to person transmission between the infected person (Transmitter) and others in shared air spaces (Recipient Cluster Chains) in these communities. This initiative will provide an improved understanding of where and when transmission occurs, the transmissibility of M. tuberculosis strains especially drug resistant ones, and the complex effect of HIV and antiretrovirals. This initiative will support multidisciplinary research studies of members of the Transmitter-Recipient Cluster Chains (TRCCs) that characterize host/pathogen/microenvironment interactions resulting in Mtb transmission in HIV-endemic settings. With improved knowledge of these interactions, novel approaches for preventing new TB infections and disease in the context of HIV infection could be developed or existing interventional strategies may be improved and adapted for a broad scale-up.

Research will be supported to characterize TB transmission events within the TRCC in HIV-endemic settings specifically in terms of:

  • Aerobiology: Studies elucidating the infectious aerosol microenvironment and overall environmental aspects that promote transmission.
  • Host factors: Studies may include identification of biomarkers of recent TB exposure/infection as well as underlying genetic or epigenetic factors and related regulatory genes and signaling pathways that play a role in changes in host responses that may determine transmission.
  • Characteristics or subpopulations of Mtb strains, including drug resistant strains, that facilitate efficient transmission (for transmitters and for those becoming infected).
  • Role of HIV in enhancing transmission (both for effects on the transmitters (e.g., aerosol infectious loads) and those at risk of becoming infected and effects of antiretroviral therapy.
  • Studies of potential new interventions to decrease human-to-human transmission. Systemic chemoprophylaxis and host-directed therapeutic agents or vaccines are not included in this funding opportunity announcement. Studies of nosocomial transmission and high-risk groups (e.g., healthcare workers) will be encouraged.

The areas below are not responsive to this funding opportunity:

  • Research proposals involving animal studies.
  • Trials of systemic chemoprophylaxis, host-directed therapeutic agents, or vaccines primarily intended to prevent progression from latent infection to active disease.

Understanding Immunopathogenesis of Tuberculosis in HIV-1 Infected and Exposed Children

Request for Applications—proposed FY 2019 initiative

Contact: Patrick Jean-Philippe

Objective:

DAIDS Priority: Establish treatment and prevention strategies for HIV-associated infections of highest morbidity and mortality, especially tuberculosis (TB).

Elucidate the pathogenic mechanisms and consequences of high-priority co-infections in the context of HIV infection.

Description: This initiative will support research to identify changes in immune mechanisms and markers as a result of Mycobacterium tuberculosis (Mtb) exposure, infection, or disease in pediatric populations that have been exposed to or infected with HIV-1. Applications should show potential for direct translation to developing immunodiagnostics, vaccines, and immunotherapeutics (host-directed strategies) specifically for the pediatric population.

The goal of this initiative is to stimulate research to elucidate TB-specific immunologic mechanisms and/or markers in pediatric populations that have been exposed to or infected with HIV. Specific areas of interest include but are not limited to:

  1. Role of innate immune mechanisms in pediatric TB and TB/HIV immunity including macrophage and dendritic cell (DC) function in the lungs and alterations in DC and macrophage pattern recognition receptor and cell signaling pathways.
  2. Evaluation of adaptive immune responses in pediatric TB and TB/HIV immunity including development of effective Th1-type and CD8+ T cell responses, quantity, and/or kinetics of their expansion, tissue homing, polyfunctionality and durability, influence of regulatory T cells, and role of humoral immunity.
  3. Characterization of innate-adaptive interface interactions and linking innate and adaptive immune responses including the role of neutrophils, natural killer (NK) cells, NK T cells, CD1 group 1-restricted T cells, gamma delta and mucosal-associated invariant T cells in pediatric TB, and TB/HIV immunity.
  4. Immune correlates of protection to TB infection and disease in HIV-1 infected, HIV-1 exposed uninfected, and HIV-1 unexposed children.
  5. Mechanism of immune tolerance in neonates and its role in TB infection. Evaluation of immunologic immaturity in neonates and young children as the cause of high susceptibility to TB in this population, including its role in shaping both innate and adaptive immune responses and alterations that compromise immunity in pediatric TB and TB/HIV.
  6. Assessing the role of trained immunity (e.g., BCG-vaccination induced) in neonatal monocytes, macrophages, and T cells, and potential consequences of altered immune host responses in pediatric TB and TB/HIV immunity.
  7. Evaluation of differences in pediatric immunity following natural infection or BCG vaccination and the influence of age (neonates versus infants) at immunization on the immune response and protection against TB induced by BCG.
  8. Immunopathogenesis of extrapulmonary TB in pediatric TB and TB/HIV.

Use of Non-Human Primate (NHP) animal models will be supported. Establishing, optimizing, or using a pediatric TB and TB/HIV NHP animal model to better understand immunologic immaturity, early immune responses, pathogenicity, and Mtb disease progression in HIV co-infection will be supported.

For research involving humans or human samples, ongoing clinical trials, prospective cohorts or other clinical or research settings, or stored blood/biologic samples from well-characterized, well-maintained repositories involving the target populations will be supported.

The target populations are children (defined as 14 years or less) exposed to or infected with Mtb who are exposed to or infected by HIV; other populations can be considered when required as comparators and with proper justification.

Applications proposing any of the following research topics will be considered non-responsive and will not be reviewed:

  • Establishing new clinical trials
  • Establishing new prospective cohorts
  • Research with non NHP animal models
  • Non-target populations or their stored samples when used as a primary focus of research

Harnessing Big Data To Halt HIV

Program Announcement With Special Receipt, Referral, and/or Review Considerations—proposed FY 2019 initiative

Contact: Rosemary Mckaig

Objective: Promote the use of big data methods to address gaps in our understanding of HIV transmission networks.

Description: This initiative will support bioinformatics data management, establishment of big data science standards, machine-learning algorithms, mathematical modeling, and consideration and application of privacy and ethical issues in the use of public and personal data in the context of HIV incidence.

Imaging the Persistent HIV Reservoir

For the published program announcement, see the June 6, 2017 Guide announcement, Imaging the Persistent HIV Reservoir (R01).

Optimizing Phylodynamics To Target and Interrogate Clusters (OPTICS)

For the published program announcement, see the June 7, 2017 Guide announcement, Optimizing HIV Phylodynamics to Target and Interrogate Clusters (OPTICS) (R21).

Content last reviewed on June 26, 2017