Magnet Grants: Attracting new expertise to HIV cure research

Overview

Purpose

To recruit data scientists, including modelers, systems biologists, and network analysts from outside the field of HIV to address questions vital to finding a cure for HIV.

Structure

Collaborations are required between an HIV scientist with access to datasets relevant to HIV and a data scientist from outside the field of HIV.

Areas of interest

Use existing datasets to identify novel:

Targetable biomarkers of the reservoir

Intrinsic or extrinsic mediators of reservoir dynamics

Features or pre-ATI predictors of curative outcomes, including:

Delay to viral rebound following antiretroviral therapy (ART) withdrawal



Sustained control of viral replication without the use of ART



Reduction in reservoir size



Viral eradication

Available funding

Total cost $150,000

Period of performance

One year, starting March 1, 2020

Due dates

REGISTRATION DEADLINE: Tuesday, November 26, 2019, 3:00 PM EASTERN TIME

APPLICATION SUBMISSION DEADLINE: Wednesday, December 11, 2019, 3:00 PM EASTERN TIME

Program Overview

Background and purpose

In the 40 years since the beginning of the HIV epidemic, and more recently since the advent of high-throughput platforms, scientists have amassed large quantities of data in their search for answers to end the epidemic. Efforts such as those of the Los Alamos National Laboratory have led to the largest, most comprehensive database on HIV sequence variability used by researchers worldwide. Host response data available at the National Center for Biotechnology contains an unbiased look at the immune response to HIV and may hold the key identifying biomarkers of the viral reservoir. Single-cell datasets available through academic collaborations describe PLWHIV with unique phenotypes such as elite and post-treatment controllers, or those with undetectable reservoirs. The increasing use of electronic medical records represents another comprehensive source of data. At the same time, new computational algorithms are providing an opportunity to deconvolute data from bulk cell processing, giving older datasets a new chance at fresh analysis. When information contained in a variety of datasets is combined with sophisticated analysis methods, powerful new information could shed light on some of the most important remaining challenges in finding a cure for HIV. Through Magnet grants, amfAR calls on HIV scientists to collaborate with data scientists from all industries, backgrounds and credentials to use any ethically sourced dataset to search for answers necessary to cure the 38M people living with HIV.

Magnet grants will propel major advances in HIV cure research by complementing the existing research capacity of biomedical cure researchers with data science experts from outside the field of HIV. The collaboration will enable transformative research projects that:

challenge assumptions

provide new perspectives

bring emerging ideas or approaches from outside HIV cure research to advance our field.

Dataset Availability

Any ethically sourced dataset may be used in the proposed work. Data may be acquired through public or private repositories or through collaborations with scientists generating the data. Priority will be placed on projects that integrate data types and sources, or otherwise advance methodology that improves our understanding of barriers to a cure.

Funding Opportunity Description

Specific areas of interest

Use existing datasets to identify novel targetable biomarkers of the reservoir

The main barrier to a cure for HIV is the presence of a viral reservoir that persists despite suppressive antiretroviral therapy (ART). The reservoir consists of HIV-infected cells that are responsible for the viral recrudescence experienced by most PLWHIV once ART is stopped. Reservoir cells may be transcriptionally silent or active. Finding biomarkers of the silent and/or active reservoir would serve as the first step in targeting it for suppression or destruction and could lead to future curative interventions.



Use existing datasets to identify novel intrinsic or extrinsic mediators of reservoir persistence

Reservoir persistence may be mediated by intrinsic and/or extrinsic factors. Intrinsic factors include processes contained within the infected reservoir cell, such as transcription, translation, or other cell processes. Extrinsic factors are those that originate outside the reservoir cell. Some of the most commonly studied extrinsic factors include the activity of CD8 T cells or antibodies. However, reservoir latency may also be modulated by non-immune cells, or soluble factors or processes. Emerging data from the cancer field suggests that the tumor microenvironment, such as osteoclasts, can significantly affect the dormancy of myeloma cells by reprogramming their gene activity. In addition, the lymph node structural environment, such as fibroblastic reticular cells, can regulate T-cell activation, which may be important for reservoir reactivation. Thus, a variety of cells, factors or processes that have received less attention in the context of HIV may have important consequences for reservoir dynamics.



Applicants are urged take a wide, unbiased view of the context in which a reservoir cell resides and consider, in addition to traditional actors on the reservoir, ‘third players’ that could be important modulators of the reservoir.



Use existing datasets to identify novel features or pre-ATI predictors of curative outcomes



Delay to HIV viral rebound following antiretroviral drug withdrawal

Some interventions, such as extremely early ART or hematopoietic stem cell transplantation, have resulted in unexpectedly long delays to rebound. Although these long delays are associated with extremely small reservoirs, it is unclear whether additional processes are responsible for controlling the remaining small reservoir of replication-competent virus. Importantly, it will be crucial to understand and predict the loss of viral control that results in the dramatic viral rebound that necessitates the re-initiation of ART. Understanding why viral control is ultimately lost will facilitate the design of an intervention that can prolong delay to, or even prevent, viral rebound.

Sustained control of viral replication without the use of antiretroviral drugs

Two rare groups of PLWHIV, elite controllers (EC) and post-treatment controllers (PTC), are able to control the virus in the absence of ART. The mechanisms of control are at least somewhat non-overlapping between EC and PTC. Features that uniquely define at least some elite controllers have been ascribed to genetics, but unbiased investigations into other correlates of control may identify previously unknown mechanisms and could lead the way to new curative interventions. It is not known whether mechanisms of control overlap among post-treatment controllers. For example, about 13% of people acutely treated for HIV become post-treatment controllers, while only 4% of people do so when treated during a chronic infection. Do the mechanisms of control overlap among all PTCs? Or even within acutely or chronically treated patients? Are there mechanisms of control shared by ECs and PTCs? Advances in understanding these mechanisms would greatly improve our ability to bring interventions that could widely induce post-treatment control to more PLWHIV.

Reduction in reservoir size

As the field strives to achieve the goal of eliminating replication-competent HIV provirus, much can be learned from interventions that reduced the size of the reservoir meaningfully. Clinical datasets from interventional trials in which meaningful reservoir reduction was observed, whether successful in delaying viral rebound or not, may hold vital information necessary for focusing the fields efforts around new or unexpected methods of reservoir reduction.

Viral eradication

To date, there is only one confirmed case of viral eradication, although other related cases appear promising. In addition, there are PLWHIV in whom it is so far impossible to detect persistent replication-competent HIV. Do these rare cases share common features that could have predicted viral eradication prior to interruption of ART, or are the predictors of viral eradication specific to the intervention? Is there a threshold reservoir size or state (e.g., anatomical or cellular location, chromatin environment, or other factors) below which the immune system or other mechanisms can eradicate the reservoir? Understanding the minimum requirements for viral eradication and methods to assess its completeness will advance the field towards this ultimate goal of cure research.

Award Information

Eligibility

Principal investigators:

Must hold a doctoral level degree

Must be from the applicant institution

Data scientist:

No specific eligibility criteria regarding the academic training are required for the data scientist. However, they must show previous achievement in their field relevant to the proposal.

Institutions:

Applications are accepted from nonprofit research institutions worldwide; applications are not accepted from individuals or for-profit entities.

Research teams may include members from, and budgets may include subcontracts or subawards to, for-profit entities.

Funding restrictions

Magnet grants provide a total cost maximum of $150,000.

Indirect costs may not be greater than 20% of direct costs, less subawards. There is no direct cost maximum.

This RFP solicits projects to be completed in the one-year period starting February 1, 2020. No-cost extensions will not be granted.

Research plan

Principal Investigators should be bold in their proposals, pursue ground breaking ideas and look to recruit data science experts from all fields and industries regardless of whether they have traditional credentials.

Proposal requirements:

The proposed research plan must be responsive to at least one specific area of interest. Research plans falling outside of the prescribed areas of interest will not be considered.

A collaborative work plan involving the HIV cure scientist and a data scientist that uses novel methods or perspectives must be proposed.

Magnet grants will fund only data analysis, not data collection. Therefore, existing datasets relevant to HIV cure must be available.

The Principal Investigator must hold a doctoral degree.

Research plans are encouraged to:

combine datasets from multiple sources

consider the relevance of the dataset(s) to clinical outcomes

Research plans should not include:

Hypothesis-driven exploration of virological or immunological markers

De novo measurement of virological or immunological outcomes

Important notes:

Applicants should ensure that the research plan is written for reviewers who are well-versed in HIV cure research and should therefore not spend unnecessary space describing common knowledge in the field.

amfAR will not consider iterations of previously tested ideas that resulted in only modest advances or studies that would result in incremental advances in knowledge.

Collaborations must be meaningful and capitalize on the verifiable expertise of both parties.

Applicants may submit inquiries to amfAR (grants@amfar.org) regarding the development of research plans to ensure that such plans fit within the intended scope of this RFP.

Application Review and Selection Process

Applications that are responsive to the RFP and are in keeping with amfAR priorities will be reviewed by members of amfAR’s Scientific Advisory Committee including senior HIV cure researchers and data scientists.

The merit of each application will be assessed with respect to:

expected impact on HIV cure



innovation and novelty of the proposed work



possible scientific or budgetary overlap

Successful applications are chosen based on reviewer comments and on amfAR priorities.

Application submission

Submission of applications is a two-step process through our online portal.

Register to receive portal log-in credentials no later than 3:00 PM Eastern Time on Tuesday, November 26, 2019.

CLICK HERE to request log-in credentials. Username, password and a link to the submission portal will be sent to the email address provided.

Use the log-in information to complete and submit the application online through the portal. Applications must be submitted no later than 3:00 PM Eastern Time on Wednesday, December 11.

Please be sure to request credentials and forms with adequate time to prepare an application. Deadline extensions will not be provided.