Two items relevant to long COVID

One of the tricky issues in studying in long COVID is: how widely do researchers cast their net? Initial reports acknowledged that people who were hospitalized and in intensive care may take a while to get back on their feet. But the number of people who had SARS-CoV-2 infections and were NOT hospitalized, yet experienced lingering symptoms, may be greater. A recent report from the United Kingdom, published in PLOS Medicine, studied more than Read more

All your environmental chemicals belong in the exposome

Emory team wanted to develop a standard low-volume approach that would avoid multiple processing steps, which can lead to loss of material, variable recovery, and the potential for Read more

Signature of success for an HIV vaccine?

Efforts to produce a vaccine against HIV/AIDS have been sustained for more than a decade by a single, modest success: the RV144 clinical trial in Thailand, whose results were reported in 2009. Now Emory, Harvard and Case Western Reserve scientists have identified a gene activity signature that may explain why the vaccine regimen in the RV144 study was protective in some individuals, while other HIV vaccine studies were not successful. The researchers think that this signature, Read more

HIV/AIDS

Signature of success for an HIV vaccine?

Efforts to produce a vaccine against HIV/AIDS have been sustained for more than a decade by a single, modest success: the RV144 clinical trial in Thailand, whose results were reported in 2009.

Now Emory, Harvard and Case Western Reserve scientists have identified a gene activity signature that may explain why the vaccine regimen in the RV144 study was protective in some individuals, while other HIV vaccine studies were not successful.

The researchers think that this signature, observed in immune cells in the blood after vaccination, could be used to design future vaccines that will have a better chance of providing protection against HIV infection.

“We may not need to take ‘shots in the dark’, when testing vaccine platforms or adjuvants for efficacy,” says senior author Rafick-Pierre Sekaly, PhD. “Instead, we can now identify adjuvants and/or vaccine regimens which more potently induce the activation of this signature.”

Rafick-Pierre Sekaly, PhD

The results, published this week in Nature Immunology, also contain hints on a contributing factor explaining why a recent HIV vaccine study conducted in South Africa (HVTN702) did not show a protective effect. HVTN702 was designed as a follow-up to RV144, but multiple parameters were different between the Thai and South African vaccine studies, such as the demographics of the participants, the adjuvant used, and the levels and varieties of HIV circulating.

“Our findings highlight one potential mechanism which may have contributed to the muted efficacy of HVTN702,” says Sekaly, professor of pathology and laboratory medicine at Emory University School of Medicine and a Georgia Research Alliance Eminent Scholar.

This mechanism involves the choice of adjuvant, a vaccine additive that enhances immune responses. While RV144 used the adjuvant alum (aluminum hydroxide), HVTN702 used the oil-based adjuvant MF59, also found in some influenza vaccines, to stimulate higher antibody production.

“There are multiple ways that a vaccine can promote protection and some of these do not involve antibodies,” Sekaly says. “Since MF59 failed to potently induce the gene signature we found to be associated with protection, this signature could guide us to mechanisms distinct from antibodies which could trigger protection from HIV-1.”

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Natural killer cells can help control virus in primate model of HIV/AIDS

A combination immunotherapy of IL-21 and IFN-alpha, when added to antiviral therapy, is effective in generating highly functional natural killer cells that can help control and reduce SIV (simian immunodeficiency virus) in animal models. This finding, from Yerkes National Primate Research Center scientists in collaboration with Institut Pasteur, could be key for developing additional treatment options to control HIV/AIDS.

The results were published in Nature Communications.

Antiviral therapy (ART) is the current leading treatment for HIV/AIDS, and is capable of reducing the virus to undetectable levels, but is not a cure and is hampered by issues such as cost, adherence to medication treatment plan and social stigma.

To reduce reliance on ART, the Yerkes, Emory and Institut Pasteur research team worked with 16 SIV-positive, ART-treated rhesus macaques. In most nonhuman primates (NHPs), including rhesus macaques, untreated SIV infection progresses to AIDS-like disease and generates natural killer (NK) cells with impaired functionality. In contrast, natural primate hosts of SIV do not progress to AIDS-like disease. Determining why natural hosts do not progress or how to stop the progression is a critical step in halting HIV in humans.

The researchers compared ART-only treated animals with animals that received ART, IL-21 and IFN-alpha to evaluate how the ART plus combination immunotherapy affected the amount of virus in the animals’ tissues.  

“Our results indicate ART plus combo-treated rhesus monkeys showed enhanced antiviral NK cell responses,” says first author Justin Harper, PhD, a senior research specialist and manager of the Paiardini research lab. “These robust NK cell responses helped clear cells in the lymph nodes, which are known for harboring the virus and enabling its replication and, therefore, the virus’ persistence. Targeting areas where the virus seeks refuge and knowing how to limit replication facilitate controlling HIV.”

HIV treatment has historically focused on the role of T cells in immunity, so harnessing NK cells opens up different avenues.

Mirko Paiardini, PhD

“This proof-of-concept study in rhesus monkeys, which progress to AIDS-like disease in the absence of ART, demonstrates how certain NK cell activities can contribute to controlling the virus,” says Mirko Paiardini, PhD, an associate professor of pathology and laboratory Medicine at Emory University and a researcher at Yerkes. “This opens the door to designing additional treatment strategies to induce SIV and HIV remission in the absence of ART, and, ultimately, reducing the burden HIV is to individuals, families and the world.”

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Repurposing a rheumatoid arthritis drug for COVID-19

For COVID-19, many researchers around the world have tried to repurpose drugs for other indications, often unsuccessfully. New clinical trial results show that baricitinib, developed by Eli Lilly and approved for rheumatoid arthritis, can speed recovery and may reduce mortality in some groups of hospitalized COVID-19 patients.

How did this study, sponsored by the National Institute of Allergy and Infectious Diseases, come together? In part, through decade-long groundwork laid by investigators at Emory, and their collaborations with others.

The ACTT-2 results were recently published in New England Journal of Medicine. (More formal NIAID and Emory press releases are here and here.)

For several years, drug hunter and virologist Raymond Schinazi and his team had been investigating a class of medications called JAK inhibitors, as an option for tamping down chronic inflammation in HIV infection. Schinazi was one of the first at Emory to investigate the use of anti-inflammatory agents for herpesviruses and HIV in combination with antiviral drugs. He believed that these viruses “hit and run,” leaving behind inflammation, even if they later go into hiding and seem to disappear.

In Schinazi’s lab, Christina Gavegnano had shown that JAK inhibitors had both anti-inflammatory and antiviral properties in the context of HIV — a project she started as a graduate student in 2010. JAK refers to Janus kinases, which regulate inflammatory signals in immune cells.

 “Our team was working on this for 10 years for HIV,” Gavegnano says. “There was a huge amount of data that we garnered, showing how this drug class works on chronic inflammation and why.” 

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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

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Low vitamin D in people with HIV: links to heart risk, immune function

In people with HIV, low vitamin D levels have been linked to thicker carotid arteries as well as a weaker comeback for the immune system after starting antiretroviral therapy.

These results, published online recently in the journal Antiviral Therapy, are the first to confirm an association between low vitamin D levels and a measure of higher cardiovascular risk in people with HIV. They also suggest that the benefits of vitamin D supplementation for people with HIV should be evaluated in a clinical trial.

Allison Ross, MD, is an infectious disease specialist in the Department of Pediatrics and the Emory-Children's Pediatric Research Center.

The advent of effective antiretroviral therapy against HIV has dramatically improved life expectancies for people with HIV over the last 15 years. The presence of HIV is known to perturb cardiovascular health, even in the absence of an active infection. Since vitamin D levels are known to have an impact on the immune system and cardiovascular disease risk, that drove infectious disease specialist Allison Ross and her colleagues to probe these connections in people living with HIV. The results were also described on the Web sites AidsMeds and NAM/AidsMap.

Ross studied a group of HIV-positive people enrolled in Case Western Reserve University’s HIV clinic in Cleveland. Colleagues from Emory and Case Western were co-authors.

They tested vitamin D levels, immune function and heart health in 149 HIV-positive people and a matched group of 34 HIV-negative people. Vitamin D levels were significantly lower in the HIV-positive group, even when controlling for known factors that affect vitamin D.

The researchers looked at how much the immune system was able to come back after starting retroviral therapy. This involves comparing someone’s lowest ever CD4 T cell count from the current CD4 count. They found that people with the poorest level of immune restoration were the most likely to have the lowest level of vitamin D. In addition, people with the lowest vitamin D levels were more than 10 times as likely to have thickening of the carotid arteries, as measured by ultrasound.

Inflammation can be a driving factor for heart disease, but in the study, low vitamin D was not linked to higher levels of inflammation markers. Additional research could determine whether those who are starting antiretroviral therapy would see better immune recovery if they took a vitamin D supplement.

Researchers at Emory have been investigating several aspects of low Vitamin D levels and their impact on health, including a connection with Parkinson’s disease. Endocrinologist Vin Tangpricha notes that Emory studies are looking at vitamin D in the context of tuberculosis, sepsis, sickle cell disease, cancer, cystic fibrosis and pain sensitivity.

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One reason why SIV-infected sooty mangabeys can avoid AIDS

Sooty mangabeys are a variety of Old World monkey that can be infected by HIV’s cousin SIV, but do not get AIDS. Emory immunologist and Georgia Research Alliance Eminent Scholar Guido Silvestri, MD, has been a strong advocate for examining non-human primates such as the sooty mangabey, which manage to handle SIV infection without crippling their immune systems. Silvestri is division chief of microbiology and immunology at Yerkes National Primate Research Center.

Research shows sooty mangabeys have T cells that can do the same job as those targeted by SIV, even if they don't have the same molecules on their surfaces

A recent paper in the Journal of Clinical Investigation reveals that sooty mangabeys have T cells that perform the same functions as those targeted by SIV and HIV, but have different clothing.

Silvestri and James Else, the animal resources division chief at Yerkes, are co-authors on the paper, while Donald Sodora at Seattle Biomedical Research Institute is senior author.

One main target for SIV and HIV is the group of T cells with the molecule CD4 on their surfaces. These are the “helper” T cells that keep the immune system humming. Doctors treating people with HIV infections tend to keep an eye on their CD4 T cell counts.

In the paper, the scientists show that sooty mangabeys infected with SIV lose their CD4 T cells, without losing the ability to regulate their immune systems. What’s remarkable here is that sooty mangabeys appear to have “double negative” or DN T cells that can perform the same functions as those lost to SIV infection, even though they don’t have CD4.

CD4 isn’t just decoration for T cells. It’s a part of how they recognize bits of host or pathogen protein in the context of MHC class II (the molecule that “presents” the bits on the outside of target cells). Somehow, the T cells in sooty mangabeys have a way to get around this requirement and still regulate the immune system competently. How they do this is the topic of ongoing research.

The authors write:

It will be important to assess DN T cells in HIV-infected patients, particularly to determine whether these cells are preserved and functional in long-term nonprogressors. These efforts may lead to future immune therapies or vaccine modalities designed to modulate DN T cell function. Indeed, the main lesson we have learned to date from this cohort of SIV-infected CD4-low mangabeys may be that managing immune activation and bolstering the function of nontarget T cells through better vaccines and therapeutics has the potential to contribute to preserved immune function and a nonprogressive outcome in HIV infection even when CD4+ T cell levels become low.

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Reassuring news on viral immunity + HIV vaccine

A recent paper in Journal of Immunology suggests that a platform for an HIV vaccine developed by Yerkes National Primate Research Center scientists won’t run into the same problems as another HIV vaccine. Postdoc Sunil Kannanganat is the first author of the JI paper, with Emory Vaccine Center researcher Rama Amara as senior author.

Harriet Robinson, MD and Rama Rao Amara, PhD

Many HIV vaccines have been built by putting genes from HIV into the backbone of another virus. Some have used a modified cold virus (adenovirus 5). The vaccine developed at Yerkes uses modified vaccinia Ankara (MVA), a relative of smallpox and chicken pox.

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Scientists still searching for HIV’s lethal ways

Guido Silvestri, MD

It’s a knotty, complex question, and one that’s nearly 30 years old: how does HIV cause AIDS? That is, how does the virus slowly destroy the immune system?

Emory immunologist and Georgia Research Alliance Eminent Scholar Guido Silvestri, MD, and his colleagues are using a method called comparative AIDS research to try and answer that question. In other words, the scientists compare humans infected with HIV who develop AIDS and nonhuman primates from Africa who are infected with SIV, or simian immunodeficiency virus.

Silvestri is chief of the Division of Microbiology and Immunology at Yerkes National Primate Research Center.

Although SIV is very similar to HIV in terms of genetic and molecular structure, once infected with this virus, the Old World Monkey, the sooty mangabey, does not get sick.

“It’s a major mystery in AIDS research because these animals have virus replication that remains active in their body as long as they’re alive,” says Silvestri. “So, it’s not just the infection and the virus replicating that kills people. There’s something more that happens.”

Silvestri describes this research in Emory University’s Sound Science.

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Federal research funding sparks economic growth

A recent report from The Science Coalition gives numerous examples of how federally funded research at universities has led to innovation, new companies, and the creation of jobs. The Sparking Economic Growth report lists the university research origins of 100 companies, including Google, Genentech, Cisco Systems and iRobot. Four Emory startup companies were highlighted among the success stories: GeoVax, Inc., Pharmasset, Inc., Syntermed, Inc., and Triangle Pharmaceuticals, which was later acquired by Gilead Sciences in California.

Emory President James Wagner wrote a followup editorial in the Atlanta Business Chronicle about the importance of scientific research in Georgia’s universities to the health of our economy.

“Atlanta can be proud that Emory University is a shining example in this report, with four highlighted successful companies that were launched because federally funded research resulted in innovative and life-saving discoveries. These four success stories only scratch the surface as examples of the more than 150 companies and the resulting 5,500 jobs created in Georgia from discoveries at its research universities.

“Since the 1990s, Emory has turned external research funding, the majority from the federal government, into more than $775 million in licensing revenues from drugs, diagnostics, devices and consumer products. This is money infused into the state’s economy that helps create jobs and educational opportunities, saves lives, and leads to more research discoveries for the benefit of all. Emory has launched 47 start-up companies and licensed 27 drugs, medical devices and diagnostics already in the marketplace and 12 more currently in human trials.”

GeoVax, Inc., is developing and testing a promising AIDS vaccine based on research at the Emory Vaccine Center and Yerkes National Primate Research Center. Gilead Sciences (from Triangle Pharmaceuticals) and Pharmasset, Inc. are creating AIDS drugs that are taken by over 90 percent of HIV-infected patients in the United States and many more around the world. Syntermed, Inc. distributes imaging software developed at Emory that helps in the diagnosis of more than four million heart disease patients every year.

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Action Cycling 200 Mile Ride Benefits AIDS Vaccine Research

Riders gather at the Hope Clinic of the Emory Vaccine Center for the final leg of their ride.

More than 130 bicyclists rode 200 miles in two days to raise $188,660 for AIDS vaccine research at the Emory Vaccine Center. The AIDS Vaccine 200 on May 22-23, sponsored by Action Cycling Atlanta, was the eighth annual ride. The series now has raised more than $680,000 for AIDS vaccine research.

This year’s riders traveled from Emory to Eatonton, Georgia, and back to Emory along with a volunteer crew.

Because of generous sponsorships, Action Cycling donates 100 percent of funds raised by participants to AIDS vaccine research. These unrestricted funds fill gaps that cannot be met by grant dollars alone.

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