Source: Thailand Medical News Jan 23, 2020 5 years, 9 months, 1 week, 5 days, 1 hour, 17 minutes ago
More than 42 million people are infected with
HIV worldwide, about 1.5 million people in the United States alone. Currently, people with
HIV take
antiretroviral therapy (
ART), which can suppress
HIV to undetectable levels in blood, but the virus persists throughout the body in
latently infected resting
CD4+ T cells. The immune system cannot recognize these cells and no current therapies can eliminate them. When ART is stopped, viral loads spike in blood. This is why people with
HIV must take ART continuously, and this
latent reservoir is considered the greatest obstacle to a cure.
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Medical scientists from the University of North Carolina at Chapel Hill and Emory University have now used a compound called
AZD5582 to activate
latently infected
CD4+ T cells at impressive levels in blood and many different tissues with no or very little toxicity.
The new research findings are published in
Nature journal.
This new research findings was accomplished at the University Of North Carolina School of Medicine in
ART-suppressed mouse models with fully functioning human immune cells, the kind typically infected with
HIV in humans. Importantly, this research was then extended in a longitudinal, multi-dose study at Emory University in
ART-suppressed rhesus macaques infected with Simian Immunodeficiency Virus (SIV). Qura Therapeutics, a partnership between scientists at UNC-Chapel Hill and ViiV Healthcare, conducted the basic science investigations that expedited the work in animal models. More research is needed before testing could begin in humans, but this work is considered a significant scientific step toward developing curative therapies.
Co-senior author Dr J. Victor Garcia, Ph.D., director of the International Center for the Advancement of Translational Science, professor of medicine and microbiology & immunology at the UNC School of Medicine told
Thailand Medical News, "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 a completely different species infected with a different virus."
Dr Ann Chahroudi, MD, Ph.D., associate professor of pediatrics at Emory and director of the Center for Childhood Infections & Vaccines at Emory and Children's Healthcare of Atlanta, is co-senior author. "
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 said. "This is an exciting scientific achievement, and we hope this will be an important step toward one da
y eradicating the virus in people living with
HIV."
This new research was made possible by the Collaboratory of AIDS Researchers for Eradication (CARE) housed at UNC-Chapel Hill and part of the Martin Delaney Collaboratories for
HIV Cure Research—the flagship
HIV cure research program supported by the National Institutes of Health (NIH) - the Emory Consortium for Innovative AIDS Research (E-CIAR) in Nonhuman Primates, also supported by NIH, Qura Therapeutics, and ViiV Healthcare.
For many years, medical scientists have been trying various l
atency reversal agents to induce
HIV out of latency so it becomes visible to the immune system, allowing an antiviral immune response to kill the virus-infected cells. Some agents focused on activating the canonical NF-kB pathway in
CD4+ T cells to drive infected cells out of
latency. But triggering that pathway involved many hundreds of genes, making such an aggressive approach too toxic.
Medical researchers at Qura Therapeutics, a partnership between UNC-Chapel Hill and ViiV Healthcare—turned their attention to the non-canonical NF-kB pathway in
CD4+ T cells.
Dr Richard Dunham, Ph.D., lead investigator at Qura Therapeutics, led studies with patients' cells necessary to show that
AZD5582, a mimetic of the Second Mitochondrial Activator of Caspases (SMACm), could serve as an effective
latency reversal agent.
AZD5582 provides a gradual but persistent activation of the non-canonical NF-kB pathway while triggering fewer human genes than other l
atency reversal agents, potentially making it much less toxic.
Dr Dunham, Director of HIV Cure at ViiV Healthcare added, "We are excited that we now, for the first time, have a simple, tractable tool to test the long-standing hypothesis that activating
latent HIV can expose the viral reservoir to clearance."
Researchers from University Of North Carolina led by Dr Garcia, an Oliver Smithies Investigator and member of the UNC Center for AIDS Research, then tested
AZD5582 in vivo using
ART-suppressed mouse models that contain human
CD4+ T cells in tissues throughout the body. Dr Garcia and colleagues documented increases in 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.
Dr Chahroudi and colleagues tested
AZD5582 in
ART-suppressed, SIV-infected macaques at Emory and found similar results, this time with multiple, weekly doses. They observed a spike in RNA expression in lymph nodes and blood of the primates, marking the first time a l
atency reversal agent accomplished this feat with little toxicity in both animal models used to study
HIV.
In another research paper in the same issue of
Nature, Emory researchers led by Dr Guido Silvestri, MD and Dr Chahroudi in collaboration with UNC researchers, accomplished latency reversal in a different way. They injected an antibody into nonhuman primates with
ART-suppressed SIV infection to deplete CD8+ T cells, which are very important for controlling the infection. Then the researchers administered an altered version of the cytokine IL-15 to show that this combination pushed viral RNA to appear in blood and tissue where it previously had not been seen. Dr Garcia and UNC colleagues confirmed these results for
HIV in the same type of mouse model in which
AZD5582 was tested.
Though it is not yet clear if the strategy of depleting CD8 cells could be translated into humans, this result opens new ways to understand how
HIV is controlled, and how its expression might be manipulated. .
These findings taken together demonstrate the power of science conducted across teams, across institutions, and between industry and academic partners. The
Nature studies show that
HIV can be pushed out of hiding—confirmed across different model systems—and the studies open a range of possibilities for the development of new therapies that might one day lead to a cure for
HIV.
References :
Systemic HIV and SIV latency reversal via non-canonical NF-κB signalling in vivo, Nature (2020). DOI: 10.1038/s41586-020-1951-3 , https://nature.com/articles/s41586-020-1951-3
Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8+ cells, Nature (2020). DOI: 10.1038/s41586-020-1946-0 , https://nature.com/articles/s41586-020-1946-0
