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 March 16, 2020 by Quinn Eastman in Immunology Leave a comment

New animal model for elimination of latent TB

The significance of a recent Tulane/Yerkes study on eradicating latent tuberculosis in non-human primates may not be apparent at first glance. After all, it used the same antibiotic regimen (isoniazid + rifapentine) that is recommended by the CDC for human use.

But consider whether someone who was exposed to TB in childhood might still have it in their lungs somewhere. It’s difficult to know if treatments get rid of the bacteria completely.

“The antibiotic treatment we used for this study is a new, shorter regimen the CDC recommends for treating humans with latent tuberculosis, but we did not have direct evidence for whether it completely clears latent infection,” says Yerkes/Emory Vaccine Center researcher Jyothi Rengarajan, who was co-principal investigator along with Deepak Kaushal of Tulane. “Our experimental study in macaques showing almost complete sterilization of bacteria after treatment suggests this three-month regimen sterilizes humans as well.”

In an editorial in the same journal, CDC and Johns Hopkins experts call the results “dramatic” and say application of the drug regimen “could presage a major step forward in TB prevention and control.” Read more

Posted on January 15, 2020 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

Posted on November 6, 2019 by Quinn Eastman in Immunology Leave a comment

Designer drugs as tools for studying brain development in non-human primates

To investigate the functions of regions within the brain, developmental neuroscience studies have often relied on permanent lesions. As an alternative to permanent lesions, scientists at Yerkes National Primate Research Center sought to test whether chemogenetic techniques could be applied to produce a transient inhibition of the amygdala, well known for regulating emotional responses, in infant non-human primates.

Their findings were recently published online by eNeuro, an open access journal of the Society for Neuroscience.

Amygdala — image from NIMH

Chemogenetics is a way of engineering cells so that they selectively respond to designer drugs, which have minimal effects elsewhere in the brain. It involves injection of a viral vector carrying genes encoding receptors responsive to the designer drug – in this case, clozapine-N-oxide, a metabolite of the antipsychotic clozapine. The technique has mostly been tested in rodents.

“This proof-of-principle study is the first to demonstrate that chemogenetic tools can be used in young infant nonhuman primates to address developmental behavioral neuroscience questions,” says Jessica Raper, PhD, first author of the eNeuro paper and a research associate at Yerkes. “Considering its reversibility and reduced invasiveness, this technique holds promise for developmental studies in which more invasive techniques cannot be employed.” Read more

Posted on October 17, 2019 by Quinn Eastman in Neuro Leave a comment

Antibody diversity mutations come from a vast genetic library

Vaccine scientists want to nudge the immune system into producing antibodies that will protect us from infection. In doing so, they are playing with fire – in a limited way. With every healthy antibody response, a process of internal evolution takes place among B cells, the immune cells that produce antibodies. It’s called “somatic hypermutation.”

In the lymph nodes, individual B cells undergo an accelerated rate of mutation. It’s as if those B cells’ DNA were being cooked with radiation or mutagenic chemicals – but only in a few genes. Then the lymph nodes select the B cells with high-affinity antibodies.

Gordon Dale, a just-defended graduate student from Joshy Jacob’s lab in Emory Vaccine Center, has a new paper in Journal of Immunology that sheds light on how somatic hypermutation takes place in both mice and humans.

In particular, Dale and Jacob found that the mutations that occur in human and mouse antibody genes are not random. They appear to borrow information from gene segments that are leftovers from the process of assembling antibody DNA in B cells.

In a mix and match process called VDJ recombination, B cells use one of many V, D, and J segments to form their antibody genes. What Dale and Jacob were looking at occurs after the VDJ step, when B cells get stimulated as part of an immune response.

They analyzed the patterns of mutations in human and mouse antibody genes, and found that mutations tend to come together, in a way that suggests that they are being copied from leftover V segments. They call this pattern “tem Read more

Posted on August 5, 2019 by Quinn Eastman in Immunology Leave a comment

When parents de-stress, so do offspring

Parents around the world can relax, knowing that their kids won’t inherit all of their stresses — at least at the DNA or epigenetic level. In an animal model, neuroscientists at Yerkes National Primate Research Center have shown they can reverse influences of parental stress by exposing parents to behavioral interventions following their own exposure to stress.

“These results in our mouse model are an important public health contribution because they provide optimism for applying similar interventional approaches in humans and breaking intergenerational cycles of stress,” says lead author Brian Dias. More information here.

The research was published in Biological Psychiatry, and is a continuation of Dias’ work with Kerry Ressler on this topic, which earned some attention in 2013. Note: the mice weren’t inheriting a fear as much as a sensitivity to a smell. Even so, it remains an intriguing example of how transgenerational (um, since the word “epigenetic” is so stretchy now) influences can be studied in a precise molecular way.

Posted on August 30, 2018 by Quinn Eastman in Neuro Leave a comment

Fragile X: preclinical portfolio for PI3k drug strategy

Research in mice shows that a pharmacological strategy can alleviate multiple behavioral and cellular deficiencies in a mouse model of fragile X syndrome (FXS), the most common inherited form of intellectual disability and a major single-gene cause of autism spectrum disorders.

The results were published online last week by Neuropsychopharmacology, and were presented at the NFXF International Fragile X Conference in Cincinnati.

When the compound GSK6A was given to mice lacking the Fmr1 gene, an established animal model of fragile X syndrome, it relieved symptomatic behaviors, such as impaired social interactions and inflexible decision making, which can be displayed by humans with fragile X syndrome.

The findings indicate that treatment with GSK6A or a similar compound could be a viable strategy for addressing cognitive and behavioral problems in fragile X syndrome; this would need to be tested directly in clinical trials. GSK6A inhibits one particular form of a cellular signaling enzyme: the p110β form of PI3 (phosphoinositide-3) kinase. A closely related p110β inhibitor is already in clinical trials for cancer.

Video from the iBook “Basic Science Breakthroughs: Fragile X Syndrome”. Narration by Emory genetics chair Stephen Warren, whose team identified the gene responsible for fragile X.

“Our results suggest that p110β inhibitors can be repurposed for fragile X syndrome, and they have implications for other subtypes of autism spectrum disorders that are characterized by similar alterations of this pathway,” says Gary Bassell, PhD, professor and chair of cell biology at Emory University School of Medicine.

“Right now, no proven efficient treatments are available for fragile X syndrome that are targeted to the disease mechanism,” says Christina Gross, PhD, from Cincinnati Children’s. “We think that p110β is an appropriate target because it is directly regulated by FMRP, and it is overactivated in both mouse models and patient cell lines.”

The paper represents a collaboration between three laboratories: two at Emory led by Bassell and Shannon Gourley, PhD, and one at Cincinnati Children’s, led by Gross. Gourley is based at Yerkes National Primate Research Center; see this earlier item on her collaboration with Bassell here.

While the researchers are discussing clinical trials of p110β inhibitors in fragile X syndrome, they say that long-term studies in animals are needed to ensure that undesirable side effects do not appear. More here.

With respect to clinical trials, the fragile X community has been disappointed before. Based on encouraging studies in mouse models, drugs targeting mGluR5 glutamate receptors were tested in adolescents and adults. mGluR5 drugs did not show clear benefits; recent re-evaluation suggests the choice of outcome measures, the ages of study participants and drug tolerance may have played a role.

Warren played a major role in developing the mGluR5 approach and Emory investigators were part of those studies. More recently, clinical trials for one of the mGluR5 medications were revived in younger children and Emory is a participating site. Also, see this 2016 discussion in Spectrum with Elizabeth Berry-Kravis on the fragile X mouse model; Bassell, Gross and Gourley have made some inroads on the limitations Berry-Kravis describes.

Posted on July 19, 2018 by Quinn Eastman in Neuro Leave a comment

Vulnerability to cocaine uncovered in adolescent mouse brains

Editor’s note: Guest post from Neuroscience graduate student Brendan O’Flaherty. Companion paper to the Gourley lab’s recently published work on fasudil, habit modification and neuronal pruning.

An Emory study has discovered why teenager’s brains may be especially vulnerable to cocaine. Exposure to small amounts of cocaine in adolescence can disrupt brain development and impair the brain’s ability to change its own habits, the study suggests.

Guest post from Brendan O’Flaherty

The results were published in the April 1, 2017 issue of Biological Psychiatry, by researchers at Yerkes National Primate Research Center.

As most of the people are approaching Sylvan Detox Center in Los Angeles to get rid off drug addiction. Shannon Gourley has shared his views on drug habit and its ill effects. Drug seeking habits play a major role in drug addiction, says senior author Shannon Gourley, PhD, assistant professor of pediatrics, psychiatry and behavioral sciences at Emory University School of Medicine and Yerkes National Primate Research Center. The first author of the paper is former Emory graduate student Lauren DePoy, PhD.

When it comes to habits, cocaine is especially sneaky. Bad habits like drug use are already very difficult to change, but cocaine physically changes the brain, potentially weakening its ability to “override” bad habits. Although adults are susceptible to cocaine’s effects on habits, adolescent brains are especially vulnerable.Hence, it is always better to seek the help of experts from Cornerstone Healing Center to get rid off drug habits.

“Generally speaking, the younger you are exposed to cocaine in life, the more likely you are to have impaired decision making,” Gourley says.

Shannon Gourley, PhD, in lab

To understand why adolescent brains are especially vulnerable to cocaine, the researchers studied the effects of cocaine exposure on how the mice make decisions about food.

“I think it’s pretty amazing that we can actually talk to mice in a way that allows them to talk back,” Gourley says. “And then we can utilize a pretty tremendous biological toolkit to understand how the brain works.”

Researchers injected adolescent mice five times with either saline or cocaine. Both groups of animals then grew up without access to cocaine. Researchers then trained the mice to press two buttons, both of which caused food to drop into the cage. Since both buttons rewarded the mice equally, the mice pushed each button half the time.

Over time, pushing the two buttons equally could become a habit. To test this, the researchers then played a trick on the mice. When one of the buttons was exposed, the researchers starting giving the mice food pellets for free, instead of rewarding them for button-pressing.

“What the mouse should be learning is: ‘Ah hah, wait a minute, when I have access to this button I shouldn’t respond, because my responding doesn’t get me anything,‘” Gourley says. Read more

Posted on December 18, 2017 by Quinn Eastman in Neuro Leave a comment

Update on SIV remission studies

Tab Ansari’s research at Emory/Yerkes on how an antibody treatment can push monkeys infected with SIV into remission was published in Science last year. At that time, Ansari told Lab Land about follow-up experiments to probe which immune cells are needed for this effect, which surprised many HIV/AIDS experts.

Ansari’s partner on the project, NIAID director Anthony Fauci, described the follow-up work in July at the International AIDS Society Conference in Paris. We thank Treatment Action Group’s Richard Jefferys for taking notes and posting a summary:

The approach that the researchers took was to deplete different types of immune cells in the animals controlling SIV viral load, then assess whether this led to an increase in viral replication. The experiments compared:

*Antibodies to the CD8 receptor alpha chain, which deplete CD8 T cells, natural killer T cells (NKTs) and natural killer (NK) cells

*Antibodies to the CD8 receptor beta chain, which deplete CD8 T cells

*Antibodies to CD20, which deplete B cells

According to Fauci’s slides, which are available online, there was a transient rebound in viral load with the CD8 alpha antibody and to a small degree with the CD8 beta. This suggests NKTs and NK cells are making a contribution to the observed control of SIV replication, but a role for CD8 T cells cannot be ruled out.

For comparison, a study from Guido Silvestri and colleagues at Yerkes published in 2016 found that treating SIV-infected monkeys with anti-CD8 antibodies, without stopping antiretroviral drugs, resulted in a rebound in virus levels. [They used ultrasensitive assays to detect the rebound.] However, the Yerkes team only used antibodies to the CD8 receptor alpha chain.

Posted on August 16, 2017 by Quinn Eastman in Immunology Leave a comment

Brain circuitry linked to social connection and desire to cuddle

Guest post from Neuroscience graduate student Amielle Moreno.

Why do scientists know more about the brain during fear than love? Behaviors such as startling and freezing in response to a fearful stimulus are rapid, vary little between subjects, and are easy to interpret. Things get messy when individuals show variability. Social behavior, like intimate partner selection and mating, has a lot of variability. To researchers willing to explore the neuroscience of love and mating, the stage is set for major discoveries.

A recent research study published in Nature from the Liu and Young laboratories at Emory and Yerkes uncovered a dynamic conversation between two brain regions during intimate behavior. The new findings in prairie voles explore the brain connections behind social connections. Read more

Posted on July 13, 2017 by Quinn Eastman in Neuro Leave a comment

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