amfAR Grants Enlist Help of Bioengineers to Overcome Obstacles to Curing HIV

In a novel approach to conquering HIV, amfAR, The Foundation for AIDS Research, is pairing HIV researchers with bioengineers to address the main barrier to a cure for HIV: the persistent reservoirs of the virus not cleared by antiretroviral therapy. A new round of Investment grants, totaling $1.2 million, will support six new research projects aimed at bringing to bear highly advanced technologies that until recently might have belonged in the pages of a science fiction novel.���
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"Over the past couple of decades, stunning advances in bioengineering have led to the development of new technologies and therapeutics that will likely have a profound impact on treating and eradicating diseases," said amfAR CEO Kevin Robert Frost. "Many of these exciting new technologies have yet to be evaluated in the realm of HIV cure research, and we hope this new round of grants lays the groundwork for some innovative approaches to a cure."
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The Investment awards are milestone-based grants that provide up to $1.5 million to each research team over four years in three phases. They are part of amfAR's $100 million Countdown to a Cure for AIDS initiative, which is aimed at developing the scientific basis of a cure by the end of 2020.�
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Bioengineers with expertise in cutting-edge technologies including microfluidics, gene-editing, nanotechnology, mass spectrometry, and single-cell magnetic levitation will work closely with leading HIV cure scientists to tackle some of the most intractable challenges in HIV cure research.��
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Magnetic levitation is a technology typically associated with high-speed transportation systems. But Timothy Henrich, M.D., of the University of California, San Francisco, and the amfAR Institute for HIV Cure Research, and bioengineer Utkan Demirci, Ph.D., from the Regents of the University of California, San Francisco, will apply a revolutionary approach called magnetic levitation of single cells to identify and characterize HIV reservoirs.

Theorizing that HIV induces a change in the magnetism and density of reservoir cells, the scientists will use a device developed by Dr. Demirci that can suspend a single cell between magnets and measure its density. Such measurements could be used to help distinguish reservoir cells from uninfected cells, and to define a molecular signature that can be targeted by curative interventions.�
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Mass spectrometry is a method of identifying and quantifying molecules that have become an indispensable tool across a broad range of fields and applications. Harnessing the technology's ability to "fingerprint" proteins, bioengineer Hui Zhang, Ph.D., and HIV scientist Weiming Yang, Ph.D., both at Johns Hopkins University in Baltimore, will use mass spectrometry to identify molecules on the surface of the cells that differentiate the latent reservoir from uninfected cells. The researchers propose that cell surface markers could aid in the development of vaccines or other interventions to target and eliminate the latent reservoir.
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"This is a very exciting round of research grants that forges some unlikely but potentially groundbreaking scientific alliances," said Rowena Johnston, Ph.D., amfAR vice president and director of research. "These highly innovative projects will undoubtedly move HIV cure research in some extraordinary new directions that, we hope, will get us closer to our goal."�

Investment grant recipients:

PI: Eli Boritz, MD PhD
Collaborating Bioengineer: David Weitz, PhD
Foundation for the NIH
$200,000�
Single-cell transcriptomic analysis of HIV reservoirs before and after systemic interleukin-2 therapy
Distinguishing the reservoir, the collection of HIV-infected cells that persist in the body, from uninfected cells is a central challenge in HIV cure research. Recently, developments in cutting-edge single-cell technologies have vastly increased the number of cells that can be analyzed. One of the pioneers in this field, Dr. David Weitz, is collaborating with Dr. Eli Boritz, an HIV scientist, to use microfluidics to scan millions of human cells for those that constitute the reservoir. Dr. Boritz proposes to use two of the most advanced microfluidic technologies, PACS and inDrop, to isolate and characterize individual reservoir cells from HIV positive people. He aims to identify the molecular signature of the reservoir so that scientists may exploit it for future curative interventions, for example by targeting interventions specifically to reservoir cells, or so that scientists can quantify the reservoir.�
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PI: Timothy Henrich, MD
Collaborating Bioengineer: Utkan Demirci, PhD
Regents of the University of California, San Francisco, San Francisco CA
$200,000�
Single-cell levitation to identify, isolate and characterize HIV reservoirs
Cells carry inherent biological properties that define their magnetism and density.�These properties may be altered if the cells encounter certain environmental stressors such as viral infection. Dr. Utkan Demirci developed a revolutionary approach called magnetic levitation of single cells, which harnesses the magnetism of cells to distinguish, for example, cancer cells from non-cancer cells. Now, in collaboration with Dr. Timothy Henrich, a member of the amfAR Institute for HIV Cure Research, Dr. Demirci is using this platform to advance the field of HIV cure research. They propose that reservoir cells can be distinguished from uninfected cells based on the change in magnetism and density induced by the virus itself. Magnetic levitation will be used to isolate the reservoir -- thereby distinguishing it from uninfected cells -- to define a molecular signature that can be targeted by curative interventions.
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PI: Keith Jerome, MD PhD
Collaborating Bioengineer: Kim Woodrow, PhD
University of Washington, Seattle WA
$200,000�
Targeted nanocarriers to accelerate depletion of the HIV reservoir
Nanoparticles, highly versatile particles that are a thousand times smaller than a cell, have been shown to be useful in applications ranging from creating synthetic skin for wound healing to cleaning up oil spills. Dr. Kim Woodrow is a bioengineer with expertise in the biomedical use of nanoparticles and has used them as biological timers to deliver pre-programmed doses of drugs. Together with Dr. Keith Jerome, an HIV cure scientist, Dr. Woodrow aims to formulate new drug combinations loaded on to nanoparticles in a two-pronged approach. First, latency-reversing agents are loaded onto the particles to reawaken the latent reservoir and prime the cell for killing by the immune system. Then the particles will carry anti-proliferative drugs that halt processes that feed and maintain the reservoir. The combined approach aims to eradicate the reservoir through direct killing by the immune system and by depriving it of what it needs to renew itself.
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PI: Priti Kumar, PhD
Collaborating Bioengineer: Mark Saltzman, PhD
Yale University, New Haven CT
$200,000�
Targeted inactivation of integrated HIV through host cell DNA repair pathways
Newly discovered gene-editing systems have energized the field of HIV cure research because of their ability to specifically target and remove HIV from the DNA. However, there are safety issues with most approaches that must be resolved before they can move into the clinic. Dr. Priti Kumar, an HIV cure scientist, proposes a gene-editing approach that solves some of the safety problems. She will use editing tools already present inside the cell and will attempt to disable the provirus by delivering a large DNA sequence that is inserted into the provirus. Her approach to increase delivery efficiency capitalizes on a collaboration with Dr. Mark Saltzman, an expert in the use of nanoparticles for drug delivery. Dr. Saltzman, utilizing FDA approved biopolymers, will engineer nanoparticles containing the 'editing instructions' and a homing device that will deliver the loaded particles specifically to the HIV reservoir. Together, they will determine whether this novel gene-editing approach using the cell's own machinery can eliminate the reservoir and cure HIV.�
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PI: Jeremy Luban, PhD
Collaborating Bioengineer: Scot Wolfe, PhD
University of Massachusetts Medical Center, Worcester MA
$200,000�
Bifunctional nucleases programmed by HIV-1 mRNA for reservoir eradication
Gene-editing systems are a promising approach to HIV cure because they are highly specific to the provirus integrated into the cell's DNA. However, molecular gene editors often force HIV to mutate its genome to evade being targeted and destroyed. Thus, the next generation of gene-editing approaches involves targeting multiple HIV-specific DNA sequences at once to prevent escape mutations by the virus. Dr. Scot Wolfe, a bioengineer with expertise in a variety of gene-editing systems, has designed a molecular editor, Cpf1, that can deliver up to 10 different instructions to edit HIV into an individual cell. Together with Dr. Jeremy Luban, an HIV scientist, they aim to use this technology to permanently disable the provirus.
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PI: Hui Zhang, PhD
Collaborating HIV Scientist: Weiming Yang, PhD
Johns Hopkins University, Baltimore MD
$199,444�
Deciphering latency-associated sugar-code to detect and eliminate latent reservoir
Reservoirs of HIV persist even during ART in part because the immune system is not able to distinguish the reservoir from uninfected cells. Identifying and exploiting differences not identified by the immune system would represent a monumental advance in HIV cure research. A powerful technique called mass spectrometry could hold the answer. Like fingerprint technology for proteins, mass spectrometry can identify the collection of molecules present on the cell surface. Dr. Hui Zhang, an expert in mass spectrometry, proposes to use this technology to identify molecules on the surface of the cells that constitute the latent reservoir. Together with Dr. Weiming Yang, an HIV scientist, Dr. Zhang proposes to identify cell surface markers that could aid the development of vaccines or other interventions to target and destroy the latent reservoir.

amfAR, The Foundation for AIDS Research, is one of the world's leading nonprofit organizations dedicated to the support of AIDS research, HIV prevention, treatment education, and advocacy. Since 1985, amfAR has invested more than $480 million in its programs and has awarded grants to more than 3,300 research teams worldwide.
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