Warren symposium follows legacy of geneticist giant

If we want to understand how the brain creates memories, and how genetic disorders distort the brain’s machinery, then the fragile X gene is an ideal place to start. That’s why the Stephen T. Warren Memorial Symposium, taking place November 28-29 at Emory, will be a significant event for those interested in neuroscience and genetics. Stephen T. Warren, 1953-2021 Warren, the founding chair of Emory’s Department of Human Genetics, led an international team that discovered Read more

Mutations in V-ATPase proton pump implicated in epilepsy syndrome

Why and how disrupting V-ATPase function leads to epilepsy, researchers are just starting to figure Read more

Tracing the start of COVID-19 in GA

At a time when COVID-19 appears to be receding in much of Georgia, it’s worth revisiting the start of the pandemic in early 2020. Emory virologist Anne Piantadosi and colleagues have a paper in Viral Evolution on the earliest SARS-CoV-2 genetic sequences detected in Georgia. Analyzing relationships between those virus sequences and samples from other states and countries can give us an idea about where the first COVID-19 infections in Georgia came from. We can draw Read more

HIV reservoir

Immunotherapy combo achieves reservoir shrinkage in HIV model

Stimulating immune cells with two cancer immunotherapies together can shrink the size of the viral “reservoir” in SIV (simian immunodeficiency virus)-infected nonhuman primates treated with antiviral drugs, Emory researchers and their colleagues have concluded. The reservoir includes immune cells that harbor virus despite potent antiviral drug treatment.

The findings, reported in Nature Medicine, have important implications for the quest to cure HIV because reservoir shrinkage has not been achieved consistently before. However, the combination treatment does not prevent or delay viral rebound once antiviral drugs are stopped. Finding an HIV cure is important because, although antiretroviral therapy can reduce the amount of circulating virus to undetectable levels, problematic issues remain such as social stigma in addition to the long-term toxicity and cost of antiretroviral drugs.

“It’s a glass-half-full situation,” says senior author Mirko Paiardini, PhD. “We concluded immune checkpoint blockade, even a very effective combination, is unlikely to achieve viral remission as a standalone treatment during antiretroviral therapy.”

He adds the approach may have greater potential if combined with other immune-stimulating agents. Or it could be deployed at a different point — when the immune system is engaged in fighting the virus, creating a target-rich environment. Other HIV/AIDS researchers have started to test those tactics, he says.

Paiardini is an associate professor of pathology and laboratory medicine at Emory University School of Medicine and a researcher at Yerkes National Primate Research Center. The study performed in nonhuman primates, considered the best animal model for HIV studies, was carried out in collaboration with co-authors Shari Gordon and David Favre at the University of North Carolina at Chapel Hill and GlaxoSmithKline; Katharine Bar at the University of Pennsylvania; and Jake Estes at Oregon Health & Science University. Read more

Posted on by Quinn Eastman in Immunology Leave a comment

Drying up the HIV reservoir

Immunologists refer to the cells that harbor HIV, even while someone is getting effective antiretroviral drugs, as the “reservoir.” That term inspires a lot of waterway metaphors! Unfortunately, drying up the HIV reservoir is not as straightforward as building a dam across a stream.  But it is the goal, if we are talking about the still-elusive possibility of a HIV cure.

Maud Mavigner, Ann Chahroudi and colleagues at Yerkes recently published a paper in Journal of Virology on targeting the Wnt/beta-catenin pathway as a tactic. They were studying SIV-infected macaques, in the context of ongoing antiretroviral therapy.

The HIV reservoir is more difficult to visualize than a human-made aquatic reservoir

Wnt is one of those funky developmental signaling pathways that gets re-used over and over again, whether it’s in the early embryo,the brain or the intestine. Beta-catenin is a central protein in that pathway.

In this case, Wnt/beta-catenin regulates the balance between self-renewal and differentiation of memory T cells – important components of the HIV reservoir. Mavigner’s team used PRI-724, a molecule that blocks interaction between beta-catenin and another protein it needs to turn on genes. PRI-724 has also been investigated in the context of cancer clinical trials. Read more

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Access to HIV’s hideouts: T cells that take on their own

Police procedural television shows, such as Law + Order, have introduced many to the Internal Affairs Bureau: police officers that investigate other police officers. This group of unloved cops comes to mind in connection with the HIV/AIDS research published this week by Rama Amara’s lab at Yerkes National Primate Research Center and Emory Vaccine Center.

“Killer” antiviral T cells (red spots) can be found in germinal centers. The green areas are B cell follicles, which HIV researchers have identified as major reservoirs for the virus. Image courtesy of Rama Amara.

HIV infection is hard to get rid of for many reasons, but one is that the virus infects the cells in the immune system that act like police officers. The “helper” CD4 T cells that usually support immune responses become infected themselves. For the immune system to fight HIV effectively, the “killer” CD8 antiviral T cells would need to take on their own CD4 colleagues.

When someone is HIV-positive and is taking antiretroviral drugs, the virus is mostly suppressed but sticks around in a reservoir of inactive infected cells. Those cells hide out in germinal centers, specialized areas of lymph nodes, which most killer antiviral T cells don’t have access to. A 2015 Nature Medicine paper describes B cell follicles, which are part of germinal centers, as “sanctuaries” for persistent viral replication. (Imagine some elite police unit that has become corrupt, and uniformed cops can’t get into the places where the elite ones hang out. The analogy may be imperfect, but might help us visualize these cells.)

Amara’s lab has identified a group of antiviral T cells that do have the access code to germinal centers, a molecule called CXCR5. Knowing how to induce antiviral T cells displaying CXCR5 will be important for designing better therapeutic vaccines, as well as efforts to suppress HIV long-term, Amara says. The paper was published in PNAS this week. Read more

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