With 38 million people infected with HIV worldwide, 1.1 million of those are in America. Presently, HIV patients are on antiretroviral therapy which can suppress HIV to undetectable levels in the blood however the virus does persist throughout the body in latently infected resting CD4+T cells. Unfortunately, the immune system can’t recognize these cells and no present-day therapies can eliminate them. Antiretroviral, required to ensure that viral loads don’t spike in the blood, is the greatest obstacle to a true cure. Enter University of North Carolina at Chapel Hill and Emory University and a compound call AZD5582 which activates latently infected CD4+ T cells at impressive levels in blood and many different tissues with no or de minimis levels.
The research effort has been carried out thus far by Qura Therapeutics, a partnership between scientists at UNC-Chapel Hill and ViiV Healthcare (joint venture of Pfizer and GSK to research a cure for HIV). The team conducted basic science investigations in an effort to expedite the work in animal models. Additional research is required however there is a growing consensus that the team is on to the right direction. Emory University has also been involved in this pursuit.
Background to Research Challenge
For nearly a decade, researchers have pursued the development of latency reversal agents to induce HIV out of latency and hence trigger visibility to the immune system. This would allow an antiviral immune response to destroy the virus-infected cells. Some agents focused on activating the canonical NF-kB pathway in CD4+ T cells to push the cells away from latency. However, the ability to trigger such a pathway involved the factoring in of many hundreds of genes, making such aggressive approach too toxic.
Enter Qura Therapeutics and their focus on the non-canonical NF-kB pathway in CD4+ T cells.
Enter Qura Therapeutics
Qura Therapeutics was formed in partnership with the University of North Carolina at Chapel Hill and GSK and is focused on finding a cure for HIV. An incredibly unique public-private partnership is redefining the traditional way of conducting clinical research and hence, is creating a new model to seek the breakthroughs needed to tackle an extraordinary challenging global health issue. Although highly active antiretroviral therapy (HAART) has offered the opportunity for most but not all infected individuals to achieve relatively normal life expectancies, there is no cure for HIV. Thus, this search for a cure for HIV infection rains a top priority of health organizations worldwide.
Qura Therapeutics offers financial and material support to the UNC HIV Cure Center to discover a cure for HIV and Qura Therapeutics will also assist in the development of therapies that emerge from the research.
To date, Qura has led studies with patients’ cells necessary to evidence that AZD5582, a mimetic of the Second Mitochondrial Activator of Caspases, could serve as an effective latency reversal agent. AZD5582 provides a gradual but persistent activation of the non-canonical NF-kB pathway while triggering few human genes than other latency reversal agents, potentially making it much less toxic.
UNC at Chapel Hill Investigator Point of View
Study co-author Dr. David Margolis, director of the University of North Carolina at Chapel Hill HIV Cure Center and the Sarah Graham Kenan Professor of Medicine, Microbiology and Immunology, and Epidemiology at UNC School of Medicine, said, “Without Qura Therapeutics, this uniquely successful academic-industry partnership, we would not have been able to get this far.”
Background to the Research
The group recently completed this feat with AZD5582 and the results were published in Nature, the UNC School of Medicine in antiretroviral therapy-suppressed mouse models with full functioning human immune cells, the kind of typically infected with HIV in humans. This study was extended in a longitudinal, multi-dose study at Emory University in antiretroviral therapy-suppressed rhesus macaques infected with Simian Immunodeficiency Virus.
The Right Direction
For example, the team noted that “previously, no one had successfully tested a latency reversal molecule in humans or in an animal model with human cells demonstrating systemic HIV induction in peripheral blood, in resting CD4+ T cells from multiple tissues, and then replicated this success in completely different species infected with a different virus,” reported J. Victor Garcia, director of the International Center for the Advancement of Translational Science and professor of medicine and microbiology and immunology at the UNC School of Medicine as well as author of the study.
Other UNC scientists tested AZD5582 in vivo using antiretroviral therapy-suppressed mouse models that contain human CD4+ T cells in tissues throughout the body. Garcia and colleagues documented increases in the viral RNA expressed in blood and nearly all tissues, including lymph nodes, thymus, bone marrow, liver, lung and brain. In some cases, the viral RNA increase was more than 20-fold.
Moreover, Dr. Ann Chahroudi, associate professor of pediatrics at Emory and director of the Center for Childhood Infections and Vaccines at Emory Children’s Healthcare of Atlanta, is co-senior author and commented “AZD5582 was remarkable in its ability to reactivate latent SIV from resting CD4+ T cells, and to induce continued virus production in the blood when monkeys were still receiving daily antiretroviral therapy.” She continued, “This is an exciting scientific achievement, and we hope this will be an important step toward one day eradicating the virus in people living with HIV.”
Over at Emory University in Georgia, investigators tested AZD5582 in ART-suppressed, SIV-infected macaques and found similar results to those in UNC at Chapel Hill but this time using multiple, weekly doses. They observed a spike in RNA expression in lymph nodes and blood of the primates, marking the first time a latency reversal agent accomplished this feat with little toxicity in both animal models used to study HIV.
What is AZD5582?
Human pancreatic cancer cells display different sensitivities to this synthetic IAP antagonist known as AZD5582. Researchers report that treating human pancreatic cancer cells with AZD5582 differentially induces apoptosis, dependent on the expression of p-Akt and p-XIAP. It targets cIAP1 to induce TNF-α-induced apoptosis. AZD5582 induces a decrease of Mcl-1 protein, a member of the Bcl-2 family, but not that of Bcl-2 and Bcl-xL. See a link to similar research into AZD5582 from Korea.
Research Funding & Contribution
The preclinical research was funded by the Collaboratory of AIDS Researchers for Eradication (housed in UNC Chapel Hill and part of the Marin Delaney Collaboratories for HIV Cure Research)—the flagship HIV cure research program supported by the National Institutes of Health and the Emory Consortium for Innovative AIDS Research in Nonhuman primates; NIH, Qura Therapeutics and ViiV Healthcare.
Summary of Findings
The overall findings evidence the power of science conducted across teams, institutions, and between industry and academic partners. These studies reveal that HIV can in fact be pushed out of hiding—confirmed across a few different model systems—and these studies, reports UNC at Chapel Hill, open a range of possibilities for the development of new therapies that might some day lead to the cure of HIV.
J. Victor Garcia, director of the International Center for the Advancement of Translational Science and professor of medicine and microbiology and immunology at the UNC School of Medicine
Dr. Ann Chahroudi, associate professor of pediatrics at Emory and director of the Center for Childhood Infections and Vaccines at Emory Children’s Healthcare of Atlanta
Call to Action: Qura Therapeutics, again representing a novel partnership at UNC at Chapel Hill, pursues the creation of a compound similar to AZD5582 with the hope of opening the first human clinical trials in 2021. Sign up for the TrialSite News Daily Newsletter for updates as they go online.