Grand Challenges is a family of initiatives fostering innovation to solve key global health and development problems. Each initiative is an experiment in the use of challenges to focus innovation on making an impact. Individual challenges address some of the same problems, but from differing perspectives.
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Adrienne Wilk of the University of Illinois at Chicago in the U.S. will investigate whether post-translational modification of S-acylated cell surface proteins alters the plasma membrane of cells with latent HIV infection. If so, these S-acylated proteins could be used to identify such latently infected cells that cannot be detected using current diagnostic methods.
Alison Hill and Daniel Scholes Rosenbloom of Harvard University in the U.S., working with Seyed Alireza Rabi and Greg Laird of Johns Hopkins University in the U.S., propose to engineer a gene therapy that delivers a viral transcription factor to reactivate CD4 cells that are latently infected with HIV along with a suicide gene that is triggered by HIV protein production to effectively kill the infected cells. This therapy could allow complete clearance of HIV from the body and a permanent cure for HIV infection.
Eugenio Montini of Fondazione Centro San Raffaele Del Monte Tabor in Italy will attempt to identify the specific cellular genes that HIV uses to integrate into cells and establish latency. Discovering these "common insertion sites" could lead to therapies for preventing HIV latency.
Seth Pincus of Children's Hospital New Orleans in the U.S., armed with knowledge that CD4+ memory cells that express the biomarker CD45RO harbor latent HIV, will test how depleting CD4+ memory cells harboring latent HIV can affect the latent HIV reservoir and the immune system in general.
Zhengxian Gu and colleagues at PTC Therapeutics, Inc. in the U.S. will investigate the mechanism of action used by a class of small molecules shown to specifically activate HIV. Understanding the pathways for reactivation of latent HIV could inform development of drug therapies to eliminate latent HIV reservoirs and effectively cure HIV.
Terri Finkel of The Children's Hospital of Philadelphia in the U.S. will test whether synthetic BET (bromodomains and extraterminal) protein antagonists can inhibit the replication of HIV and the establishment of latency, while also promoting the reactivation of latently infected cells. Such molecules could be used to control and cure HIV infection.
Phillip M. Gerk of Virginia Commonwealth University in the U.S. will test the ability of fatty acid transporters to deliver antiretroviral drugs to the central nervous system and gut-associated lymphatic tissues, which provide sanctuary for latent HIV.
Thor Wagner of Seattle Children's Hospital in the U.S. will use high-throughput single-cell screening of activated B-cells from HIV patients on antiretroviral therapy in an effort to identify antibodies that bind specifically to HIV-infected cells. These antibodies could be used to develop antibody drug conjugates to kill HIV-infected cells.
Kathryn Miller-Jensen of Yale University in the U.S. will test the hypothesis that latently infected HIV cells produce different protein phosphorylation signatures than uninfected cells in response to drug treatments. Identifying these latent HIV cells will enable the design of new therapies that selectively target and purge these latent reservoirs.
Russell Poulter of the University of Otago in New Zealand will use a microbial biosynthesis platform to develop cyclic analogues of the viral protein Tat, which is major regulator of HIV transcription, and test their ability to activate latent HIV. The reactivated HIV would be susceptible to retroviral therapies enabling comprehensive killing of HIV infected cells.