Tag Archives: Chemotherapy

Microbiology

Antiviral drugs may be a new treatment strategy in the fight against Candida auris

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Reviewed by Megan Craig, M.Sc.May 25 2023

Antiviral drugs can make antifungals work again.

That, at its simplest, is the approach Mohamed Seleem’s lab at the Center for One Health Research has found may be a key treatment strategy in the battle against Candida auris, a frighteningly deadly fungal pathogen discovered in 2009 that is considered an urgent threat by the Centers for Disease Control and Prevention (CDC).

Candida auris, first discovered in Japan as an ear infection, has a staggering 60 percent mortality rate among those it infects, primarily people with compromised health in hospitals and nursing homes.

Recently, Seleem and Ph.D. students Yehia Elgammal and Ehab A. Salama published a paper in the American Society for Microbiology’s Antimicrobial Agents and Chemotherapy journal detailing the potential use of atazanavir, an HIV protease inhibitor drug, as a new avenue to improving the effectiveness of existing antifungals for those with a Candida auris infection.

A perfect storm of antimicrobial resistance, global warming and the COVID-19 pandemic has resulted in the rapid spread of Candida auris around the world, said Seleem, director of the center, a collaboration between the Virginia-Maryland College of Veterinary Medicine and the Edward Via College of Osteopathic Medicine.

We don’t have lots of drugs to use to treat fungal pathogens. We have only three classes of antifungal drugs. With a fungal pathogen, it’s often resistant to one class, but then we have two other options. What’s scary about Candida auris is it shows resistance to all three classes of the antifungal.

The CDC has a list of urgent threats, but on that list there is just one fungal pathogen, which is Candida auris. Because it’s urgent, we need to deal with it.”

Mohamed Seleem, the Tyler J. and Frances F. Young Chair in Bacteriology at Virginia Tech

Widespread use of fungicides in agriculture, in addition to the three classes of antifungal drugs used widely in medicine, has contributed to fungal pathogens developing more resistance, particularly Candida auris.

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Also, its rise has been linked to rising global temperatures and to easier spread through hospitals filled with COVID-19 patients in recent years during the global pandemic.

Atazanavir, an HIV protease inhibitor drug, has been found by Seleem’s lab to block the ability of Candida auris to excrete antifungals through its efflux pumps.

Think of a boat taking on water and hoses siphoning that water out of the boat to keep it afloat. Atazanavir stops up the hoses.

That allows the azole class of antifungal drugs to not be expelled as easily and perform better against Candida auris, the Seleem lab’s research has found.

The research on atazanavir builds on work three years ago by Seleem’s lab, then at Purdue University, finding potentially similar benefit in lopinavir, another HIV protease inhibitor.

HIV protease drugs are already in wide use among HIV patients, who can also be extra susceptible to Candida auris. Some HIV patients have likely been taking HIV protease drugs and azole-class antifungals in tandem for separate purposes, providing a potential source of already existing data that can be reviewed on whether those patients had Candida auris and what effects the emerging pathogen had on them.

Repurposing drugs already on the market for new uses can allow those treatments to reach widespread clinical use much more rapidly than would happen with the discovery of an entirely new drug, as existing drugs have already been tested and approved by the Food and Drug Administration and have years of further observation of effects in prescriptive use.

In 2022, the Center for One Health Research received a $1.9 million grant from the National Institutes of Health for the Seleem lab’s research on repurposing already approved drugs for treating gonorrhea.

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Source:

Virginia Tech

Microbiology

Researchers report surprising first steps that promote resistance to commonly prescribed antibiotics

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Reviewed by Emily Henderson, B.Sc.Mar 31 2023

Antibiotic resistance is a global health threat. In 2019 alone, an estimated 1.3 million deaths were attributed to antibiotic resistant bacterial infections worldwide. Looking to contribute a solution to this growing problem, researchers at Baylor College of Medicine have been studying the process that drives antibiotic resistance at the molecular level.

They report in the journal Molecular Cell crucial and surprising first steps that promote resistance to ciprofloxacin, or cipro for short, one of the most commonly prescribed antibiotics. The findings point at potential strategies that could prevent bacteria from developing resistance, extending the effectiveness of new and old antibiotics.

Previous work in our lab has shown that when bacteria are exposed to a stressful environment, such as the presence of cipro, they initiate a series of responses to attempt to survive the toxic effect of the antibiotic.”

Dr. Susan M. Rosenberg, co-corresponding author, Ben F. Love Chair in Cancer Research and professor of molecular and human genetics, biochemistry and molecular biology and molecular virology and microbiology at Baylor

She also is program leader in Baylor’s Dan L Duncan Comprehensive Cancer Center (DLDCCC). “We discovered that cipro triggers cellular stress responses that promote mutations. This phenomenon, known as stress-induced mutagenesis, generates mutant bacteria, some of which are resistant to cipro. Cipro-resistant mutants keep on growing, sustaining an infection that can no longer be eliminated with cipro.”

Cipro induces breaks in the DNA molecule, which accumulate inside bacteria and consequently trigger a DNA damage response to repair the breaks. The Rosenberg lab’s discoveries of the steps involved in stress-induced mutagenesis revealed that two stress responses are essential: the general stress response and the DNA-damage response.

Some of the downstream steps of the process that leads to increased mutagenesis have been revealed previously by the Rosenberg lab and her colleagues. In this study, the researchers discovered the molecular mechanisms of the first steps between the antibiotic causing DNA breaks and the bacteria turning on the DNA damage response.

“We were surprised to find an unexpected molecule involved in modulating DNA repair,” said first author Dr. Yin Zhai, postdoctoral associate in the Rosenberg lab. “Usually, cells regulate their activities by producing specific proteins that mediate the desired function. But in this case, the first step to turn on the DNA repair response was not about activating certain genes that produce certain proteins.”

Instead, the first step consisted of disrupting the activity of a protein already present, RNA polymerase. RNA polymerase is key to protein synthesis. This enzyme binds to DNA and transcribes DNA-encoded instructions into an RNA sequence, which is then translated into a protein.

“We discovered that RNA polymerase also plays a major role in regulating DNA repair,” Zhai said. “A small molecule called nucleotide ppGpp, which is present in bacteria exposed to a stressful environment, binds to RNA polymerase through two separate sites that are essential for turning on the repair response and the general stress response. Interfering with one of these sites turns off DNA repair specifically at the DNA sequences occupied by RNA polymerase.”

“ppGpp binds to DNA-bound RNA polymerase, telling it to stop and backtrack along the DNA to repair it,” said co-corresponding author Dr. Christophe Herman, professor of molecular and human genetics, molecular virology and microbiology and member of the DLDCCCC. The Herman lab found the repair-RNA-polymerase connection previously, reported in Nature.

Rosenberg’s lab discovered that DNA repair can be an error-prone process. As repair of the broken DNA strands progresses, errors occur that alter the original DNA sequence producing mutations. Some of these mutations will confer bacteria resistance to cipro. “Interestingly, the mutations also induce resistance to two other antibiotic drugs the bacteria have not seen before,” Zhai said.

“We are excited about these findings,” Rosenberg said. “They open new opportunities to design strategies that would interfere with the development of antibiotic resistance and help turn the tide on this global health threat. Also, cipro breaks bacterial DNA in the same way that the anti-cancer drug etoposide breaks human DNA in tumors. We hope this may additionally lead to new tools to combat cancer chemotherapy resistance.”

Other contributors to this work include P.J. Minnick, John P. Pribis, Libertad Garcia-Villada and P.J. Hastings, all at Baylor College of Medicine.

Source:

Baylor College of Medicine

Journal reference:

Zhai, Y., Minnick, P. J., Pribis, J. P., Garcia-Villada, L., Hastings, P. J., Herman, C., & Rosenberg, S. M. (2023). ppGpp and RNA-polymerase backtracking guide antibiotic-induced mutable gambler cells. Molecular Cell. doi.org/10.1016/j.molcel.2023.03.003.

Microbiology

Harnessing power of immune system may lessen reliance on antibiotics for infections like TB

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Researchers at the Francis Crick Institute have found that the body’s process of removing old and damaged cell parts, is also an essential part of tackling infections that take hold within our cells, like TB.

If this natural process can be harnessed with new treatments, it could present an alternative to, or improve use of antibiotics, especially where bacteria have become resistant to existing drugs.

In their study, published in Nature Microbiology today, ahead of World TB Day on the 24th March, the team studied genes key to bacteria’s ability to evade autophagy, a pathway that cells use to destroy themselves when they are under stress or infected.

They engineered human immune cells called macrophages from specialist stem cells called induced pluripotent stem cells, which have the ability to become any cell type in the body. They then used genome editing tools to manipulate the macrophages ability to perform autophagy. When genes key to autophagy were removed and the cells were infected with Mycobacterium tuberculosis (bacilli that cause TB), the bacterial infection took hold, replicating more within the engineered cells and causing mass host cell death.

These results are evidence for a strong role of autophagy in controlling intracellular infections like TB. If this pathway can be boosted or strengthened, it could be a new avenue for tackling antibiotic resistance, by making existing antibiotic drugs more effective or presenting an alternative to drugs in cases where bacteria have evolved resistance.

Max Gutierrez, head of the Host-Pathogen Interactions in Tuberculosis Laboratory at the Crick, said: “I first studied the role of autophagy in infection during my PhD, so it’s incredible to see renewed interest in this field. Using the latest technologies, we’ve been able to show a key role for this pathway in controlling infection.

“As immunotherapies have harnessed the immune system to fight cancer, boosting this immune defence with a host-directed therapy, could be a valuable new tool in the fight against infections, particularly those becoming resistant to antibiotics.”

The team also validated their results using macrophages isolated from blood samples, confirming the importance of autophagy in human defences.

Beren Aylan, joint first author and PhD student at the Crick together with Elliott Bernard and Enrica Pellegrino, said: “Antibiotic resistance is a huge threat to our health so it’s incredibly important to understand how our bodies fight infection and where there might be room for improvement.

“TB is a great example of where targeting our own immune defences could be really effective, because it takes a very long course of different antibiotic treatments to effectively remove the infection. Anything that can be done to more effectively remove bacteria, could also make a huge difference to the cost and accessibility of treatments.”

The team are now planning to screen for drug compounds that could be used to boost autophagy in a targeted way.

“Boosting the autophagy pathway isn’t as simple as it might seem,” adds Max. This is because all parts of the body use autophagy as a way to recycle old and damaged cells. In order to safely increase autophagy in the location of infections, we need to target the pathway in macrophages alone.”

  • Beren Aylan, Elliott M. Bernard, Enrica Pellegrino, Laure Botella, Antony Fearns, Natalia Athanasiadi, Claudio Bussi, Pierre Santucci, Maximiliano G. Gutierrez. ATG7 and ATG14 restrict cytosolic and phagosomal Mycobacterium tuberculosis replication in human macrophages. Nature Microbiology, 2023; DOI: 10.1038/s41564-023-01335-9

    • The Francis Crick Institute
    Microbiology

    Study finds two substances capable of inhibiting proliferation of glioblastoma cells

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    Reviewed by Emily Henderson, B.Sc.Mar 7 2023

    Glioblastoma is a malignant tumor of the central nervous system (brain or spinal cord) and one of the deadliest types of cancer. Few drugs have proved effective at combating this uncontrolled growth of glial cells, which anyway constitute a large proportion of the brain tissue in mammals. The standard treatment is surgical removal of the tumor, followed by chemotherapy with temozolomide, radiation therapy, and then nitrosoureas (such as lomustine). Patient survival has improved moderately over the years, but the prognosis remains poor. These tumors are typically resistant to existing drugs and often grow back after surgery.

    Promising results have now been reported in a study involving two substances found to inhibit proliferation of glioblastoma cells. An article on the study is published in the journal Scientific Reports.

    The researchers conducted in vitro tests to evaluate the biological effects of 12 compounds obtained through total synthesis of apomorphine hydrochloride against glioblastoma cells. They found that two of these compounds – an isoquinoline derivative called A5 and an aporphine derivative called C1 – reduced the viability of glioblastoma cells, suppressed the formation of new tumor stem cells and boosted the effectiveness of temozolomide.

    More research is needed to glean a better understanding of the action of these compounds on tumor cells and normal cells, but the results so far suggest a potential therapeutic application as novel cytotoxic agents to control glioblastomas.”

    Dorival Mendes Rodrigues-Junior, first author of the article and postdoctoral researcher, University of Uppsala’s Department of Medical Biochemistry and Microbiology, Sweden

    In designing the study, the researchers leveraged the apomorphine hydrochloride production process, in which each step in a sequence of chemical reactions creates compounds that are consumed in the next step. Previous research conducted by the group to evaluate the effectiveness of 14 of these compounds against head and neck squamous cell cancer had shown that A5 and C1 were promising, and they decided to conduct more tests. “Given the importance and urgency of identifying novel therapeutic substances that can be used to treat glioblastoma, we evaluated the same panel as in the previous study but now for this other type of tumor,” Rodrigues-Junior said.

    The project on molecular markers of head and neck cancer was supported by FAPESP and also involved André Vettore, another author of the recently published article. Vettore is a professor in the Department of Biological Sciences at the Federal University of São Paulo (UNIFESP) in Diadema, Brazil.

    “The findings of this study are interesting, but they’re only the first steps in a long journey. In vivo studies are still required to confirm the effects of A5 and C1 on glioblastoma cells and non-tumorigenic nerve cells,” Vettore said.

    If the results of this future research are also promising, he added, it will be possible to move on to clinical trials to confirm the effectiveness of the compounds. “Once all these stages are completed, the compounds may finally be used to treat glioblastoma patients.”

    Natural bioactive products

    The study was conducted in vitro to evaluate the antitumor activity of 12 aromatic compounds obtained as intermediates in total synthesis of apomorphine, an alkaloid that interacts with the dopamine pathway and is widely used to control the motor alterations caused by Parkinson’s disease.

    Alkaloids are a well-known class of natural products with multiple pharmacological properties and are studied for their anticonvulsant, antiplatelet aggregation, anti-HIV, dopaminergic, antispasmodic and anticancer effects.

    FAPESP fosters studies of these substances via a project on bioactive natural products led at UNIFESP’s Department of Chemistry in Diadema by Cristiano Reminelli, second author of the Scientific Reports article. The other authors are Haifa Hassanie, Gustavo Henrique Goulart Trossini, Givago Prado Perecim, Laia Caja and Aristidis Moustakas.

    Source:

    São Paulo Research Foundation (FAPESP)

    Journal reference:

    Rodrigues-Junior, D.M., et al. (2023) Aporphine and isoquinoline derivatives block glioblastoma cell stemness and enhance temozolomide cytotoxicity. Scientific Reports. doi.org/10.1038/s41598-022-25534-2.

    Microbiology

    Study provides an explanation and potential solution for severe graft-versus-host disease

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    The severity of immune-mediated intestinal diseases such as graft-versus-host disease (GVHD) or inflammatory bowel diseases is known to be associated with alterations in the gut microbiome, but what leads to such disruption in the microbial community has remained a mystery.

    Researchers at Baylor College of Medicine, the University of Michigan and collaborating institutions working with animal models of GVHD report today in the journal Immunity that alterations in the gut microbiome are connected to an increase in oxygen levels in the intestine that follows immune-mediated intestinal damage. Pharmacologically reducing intestinal oxygen levels alleviated the microbial imbalance and reduced the severity of the intestinal disease.

    “There is a lot of data showing that microbes change in many diseases, but we do not understand how that happens,” said leading author Dr. Pavan Reddy, professor and director of Baylor’s Dan L Duncan Comprehensive Cancer Center, who was at the University of Michigan during the development of this project. “This study is one of the first to provide an explanation and a potential solution for the imbalance in the gut microbiome that exacerbates GVHD and possibly other inflammatory intestinal conditions.”

    GVHD is a potentially life-threatening complication of bone marrow transplantation. “It is the complication that can prevent us from using this therapy that has proven to be effective to treat many blood cancers and inherited blood diseases,” Reddy said. “The idea is to understand what makes GVHD worse so we can effectively control it. The study also is relevant to more common inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis.”

    Reddy and his colleagues discovered that the damage immune cells cause to intestinal cells prevents these cells from fully using oxygen to conduct their normal functions. Consequently, all the oxygen that is not being used by intestinal cells oozes into the intestine, changing the environment for the resident microbes.

    “Most of the ‘good microbes’ we have in the intestine grow in oxygen-poor environments — oxygen is toxic to them. They are called anaerobic (without oxygen) bacteria,” Reddy said. “When oxygen levels in the intestine increase, these microbes tend to disappear, and oxygen-loving microbes tend to grow. An increase in oxygen level provides an explanation for the microbiome changes in the context of these inflammatory diseases.”

    The findings suggested that restoring the normal environment by reducing the oxygen level in the intestine could help reestablish the balance of the microbial community and lead to attenuation of GVHD.

    “Indeed, we discovered that reducing the intestinal oxygen level actually made a difference in the progression of GVHD in the animal models,” Reddy said. “We found that a commonly used drug to reduce iron overload, an iron chelator, mitigated the microbial imbalance and reduced the severity of GVHD.”

    Iron chelators have been used for many years to treat conditions in which excess iron causes tissue damage, such as hemochromatosis. Iron chelators are compounds that bind to iron, pulling it out and removing it from the body. “We discovered that iron chelators also can act as oxygen sinks,” Reddy said. “In our animal models, iron chelators removed iron from the intestine and that facilitated the restoration of an oxygen-poor environment that gave anaerobic bacteria an opportunity to bloom. Importantly, this reduced the severity of GVHD.”

    The researchers’ next steps include conducting studies to determine whether iron chelation can help control the severity of GVHD in patients who have received a bone marrow transplant.

    Another advantage of iron chelation would be that it may reduce or avoid the use of immune suppressor medications that are usually used to control GVHD. Suppressing the immune system may control GVHD, but also favors infections, which can be life-threatening. “If iron chelation helps control the condition in patients, it would be a novel non-immunosuppressive approach to treat GVHD with seemingly little side effects,” Reddy said.

    Other contributors to this work include Keisuke Seike, Anders Kiledal, Hideaki Fujiwara, Israel Henig, Marina Burgos da Silva, Marcel R.M. van den Brink, Robert Hein, Matthew Hoostal, Chen Liu, Katherine Oravecz-Wilson, Emma Lauder, Lu Li, Yaping Sun, Thomas M. Schmidt, Yatrik M. Shah, Robert R. Jenq and Gregory Dick. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, University of Michigan, Okayama University Hospital, Rambam Health Care Campus-Israel, Memorial Sloan Kettering Cancer Center, Yale University School of Medicine and MD Anderson Cancer Center.

    This work was supported by the US National Institutes of Health grants P01HL149633, HL152605, CA217156, R01CA148828, 4 R01CA245546 and R01DK095201. Further support was provided by National Cancer Institute award numbers R01-CA228358, R01-CA228308, P30 CA008748 MSK Cancer Center Support Grant/Core Grant and P01-CA023766; National Heart, Lung, Blood Institute award number R01-HL123340 and R01- 8 HL147584; Tri-Institutional Stem Cell Initiative and NIH grant CA46592.

  • Keisuke Seike, Anders Kiledal, Hideaki Fujiwara, Israel Henig, Marina Burgos da Silva, Marcel R.M. van den Brink, Robert Hein, Matthew Hoostal, Chen Liu, Katherine Oravecz-Wilson, Emma Lauder, Lu Li, Yaping Sun, Thomas M. Schmidt, Yatrik M. Shah, Robert R. Jenq, Gregory Dick, Pavan Reddy. Ambient oxygen levels regulate intestinal dysbiosis and GVHD severity after allogeneic stem cell transplantation. Immunity, 2023; DOI: 10.1016/j.immuni.2023.01.007

    • Baylor College of Medicine
    Microbiology

    Study reveals subtypes and EBV-associated regulatory epigenome reprogramming in nasopharyngeal carcinoma

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    Reviewed by Emily Henderson, B.Sc.Dec 16 2022

    Researchers from the Department of Clinical Oncology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong (HKUMed) discovered a novel subtype of Epstein-Barr Virus (EBV)-positive nasopharyngeal carcinoma (NPC) and EBV-associated immunosuppression in the tumor microenvironment (TME). These findings have provided novel insights into the traditional NPC pathogenesis model and highlights EBV-specific communications in the TME as potential therapeutic target in NPC. The research has been published in eBioMedicine.

    Background and research findings

    NPC has a high incidence rate in Southeast Asia, in particular Guangdong and Hong Kong. Due to its worldwide rarity, studies on NPC heavily rely on local research teams, and its pathogenesis mechanism remains largely unclear. In Hong Kong, NPC is the commonest cancer type for the men aged 20-44 and ranked 8th highest incidence rate among males. Strikingly, EBV is detected in 95% of the Hong Kong cases. Having thorough understanding of NPC pathogenesis, in particular the role of EBV, is critical for advancing the clinical diagnosis and treatment for this deadly disease and is an active research topic in the field.

    The research team used a cutting-edge bioinformatics approach to comprehensively decode the epigenetics of the tumors dissected from NPC patients. EBV+NPC was believed to be massively dysregulated by the global DNA hypermethylation, a phenomenon that denotes a large-scale increase of methyl groups onto the DNA sequences within the cancer cells. These methyl-groups function like an ‘off-switch’ to inactivate tumor-suppressors that safeguard the cells from turning into a tumor, and thereby, promoting tumor development. Moreover, global DNA hypermethylation is rarely observed in non-EBV cancer types proposed to be associated with EBV and is a critical step in NPC pathogenesis.

    The research team discovered that, in contrast to what was commonly believed, 20% of NPC cases were characterized by global DNA hypomethylation, which refers to a large-scale decrease of methyl groups onto the DNA sequences in the cancer cells. The study also discovered that EBV may reprogram the cell-cell communications[4]between the cancer cells and the immune cells, and consequently protect the cancer cells from being destroyed by the immune system.

    Significance of the study

    ‘Commonly infected by EBV, the NPC tumours carried distinctive methylation patterns. This finding is not well-recognised by the NPC development model. When global DNA hypomethylation occurs during NPC pathogenesis, whether it occurs as an alternative pathway in a subset of patients and its potential of predicting patients’ survival, clinical features, and response to therapies are critical for understanding NPC and providing personalized treatments for patients.’ commented Dr Dai Wei, Assistant Professor of the Department of Clinical Oncology, School of Clinical Medicine, HKUMed.

    Professor Maria Li Lung, Emeritus Professor of the Department of Clinical Oncology, School of Clinical Medicine, HKUMed, added, ‘Since the immunosuppressive cell-cell communications were associated with EBV, these communications are highly-specific to the tumours and could be potential therapeutic targets and biomarkers in NPC.’ ‘We are now designing experiments to explore this feasibility and understand the clinical impacts of NPC subtypes. We hope the work can be beneficial to NPC patients in Hong Kong.’

    About the research team

    This research was co-supervised by Dr Dai Wei, Assistant Professor, and Professor Maria Li Lung, Emeritus Professor of the Department of Clinical Oncology, School of Clinical Medicine, HKUMed. Dr Larry Chow Ka-yue and Mr Dittman Chung Lai-shun from the Department of Clinical Oncology, School of Clinical Medicine, HKUMed, are the co-first authors, Dr Tao Lihua, Scientific Officer, provided support to the research.

    The collaborators included Dr Chan Kui-fat and Dr Stewart Tung Yuk from Department of Clinical Oncology and Department of Clinical Pathology from the Tuen Mun Hospital, Hong Kong; Professor Roger Ngan Kai-cheong, Professor Ng Wai-tong, Professor Anne Lee Wing-mui, Professor Dora Kwong Lai-wan, Dr Victor Lee Ho-fun and Dr Lam Ka-on from the Department of the Clinical Oncology, School of Clinical Medicine, HKUMed; Dr Yau Chun-chung from Department of Oncology from Princess Margaret Hospital, Hong Kong; Professor Chen Honglin and Dr Liu Jiayan from Department of Microbiology, School of Biomedical Sciences, HKUMed.

    Source:

    The University of Hong Kong

    Journal reference:

    Chow, L. K-Y., et al. (2022) Epigenomic landscape study reveals molecular subtypes and EBV-associated regulatory epigenome reprogramming in nasopharyngeal carcinoma. eBioMedicine. doi.org/10.1016/j.ebiom.2022.104357.

    Microbiology

    Miracles Start in the Lab: the quest to find a vaccine to cure AIDS

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    Danielle Ellis, B.Sc.Interview conducted by Danielle Ellis, B.Sc.Nov 30 2022
    Thought LeadersDr. Larry CoreyProfessor and President and Director EmeritusFred Hutch Cancer Center

    To commemorate World AIDS Day, News Medical spoke to Dr. Larry Corey, an internationally renowned expert in virology, immunology, and vaccine development, and the former president and director of Fred Hutch, about his work within the field of HIV/AIDS research and vaccine development. 

    Please can you introduce yourself and tell us about your background in virology, immunology, and vaccine development?  

    I’m Dr. Larry Corey. I am a Professor at the University of Washington and Fred Hutchinson Cancer Center. I am a virologist by training. I have worked in the field of HIV since the inception of the recognition of the virus. Initially, I was the leader of the US government’s AIDS Clinical Trials Group, which was devoted to antiviral chemotherapy. I was lucky early in my career to be involved in developing the first effective antiviral drug called Acyclovir, which was for herpes virus infections, especially genital herpes.

    I switched my interests in the late 1990s from therapy to try and develop an HIV vaccine and founded the HIV Vaccine Trials Network with my friend and colleague Tony Fauci. We’ve worked together to develop an HIV vaccine and set up a network within the US of investigators to tackle the immunology of HIV, which has been very formidable. The network has been where probably 80 or 90% of the HIV vaccine clinical trials have been conducted worldwide over the last 20 years.

    How have you seen the field of HIV/AIDS research change in this time? How have patient outcomes changed?

    HIV is still a pandemic illness. We still have 1.4 million new infections each year. We have a growing number of people living with AIDS, and it is still a perfect storm. You acquire it subclinically, transmit it subclinically, and get it from people you don’t suspect have it. We still need better prevention methods.

    Antiretrovirals have saved more lives than any other medical procedure or medical group of therapies in the last 50 or 60 years. We went from a disease that killed everybody to now a disease that, if you take the pills, you can live a normal lifespan essentially. That’s an amazing feat that occurred in the decade from the virus’s isolation.

    Image Credit: PENpics Studio/Shutterstock.com

    Image Credit: PENpics Studio/Shutterstock.com

    HIV research has markedly changed and become markedly more sophisticated. We’re cloning B-cells in the germ lines. We’re doing things you couldn’t conceive 40 years ago. Certainly, a vaccine will be needed to end AIDS and have my granddaughters grow up like I grew up, not worrying about AIDS.

    Patient outcomes for treatment have markedly changed. You can live normal lives. But we haven’t made as many inroads in prevention. The reason is that we don’t have a vaccine. When you look at how to prevent disease acquisition on a population basis, it’s only been with a vaccine. So, as hard as it is, the vaccine effort must continue.

    In your lab, you study genetically modified T cells to treat HIV-1. How have recent advancements in cancer treatment influenced the treating HIV/AIDS? How can immunological approaches treat chronic viral infections?

    In oncology, using the cell as an anti-tumor drug in CAR T-cell therapy is the biggest advance. The lab is trying to take those approaches used in cancer and employ them against HIV through these adopted transfer experiments. We think we’ve had some successes, so that’s our area of interest at the moment.

    You are also the principal investigator of the Fred Hutch-based operations center of the COVID-19 Prevention Network. How has the COVID-19 pandemic impacted HIV/AIDS research?

    People working in HIV and the infrastructure from HIV helped the effort against COVID-19. RNA, used in the COVID-19 mRNA vaccines, can allow experiments to be conducted more quickly because it’s synthetic, and you can make a vaccine and get it into humans by doing an early clinical trial. From the idea to putting a jab in your arm, that’s still not happening as quickly with HIV as it did for COVID-19. Still, it is quicker, and we’re optimistic that this RNA technology will help us develop an HIV vaccine quicker.

    The HVTN’s goal is to develop a safe, effective vaccine to prevent HIV globally. How close are we to actualizing this goal? From a global perspective, what would it mean to have an effective vaccine?

    We make these vaccines that elicit broadly neutralizing antibodies. If we do, we’ll get there because we’ve already proven that broadly neutralizing antibodies can prevent HIV acquisition. Now the issue is how do we get to that target now that we know what the target is? You need to be optimistic. Miracles start in the lab.

    The theme of this year’s World AIDS Day is “Equalize.” What does this theme mean to you personally? What needs to be done to address inequalities and help end AIDS?

    Everybody wants to be healthy. I think equalize is a great word for World AIDS Day. I think HIV has always been a disease of the underdog.

    Image Credit: fizkes/Shutterstock.com

    Image Credit: fizkes/Shutterstock.com

    But words have meaning and should be actionable. I think the word equalize is just another call to how we actualize the tools and maximize the use of the tools we have. COVID-19 has taught us that even if research invents a remarkably good vaccine, the process of implementing this on a population basis is complicated and needs to be equalized between the haves and the have-nots. The sociology and economics of health need to be equalized globally.

    What is next for yourself and your research?

    I’ve got my hands full trying to make an HIV vaccine.

    Where can readers find more information?

    About Dr. Larry Corey

    Dr. Larry Corey is an internationally renowned expert in virology, immunology and vaccine development, and the former president and director of the Fred Hutchinson Cancer Research Center. His research focuses on herpes viruses, HIV, the novel coronavirus and other viral infections, including those associated with cancer. He is principal investigator of the HIV Vaccine Trials Network (HVTN), which conducts studies of HIV vaccines at over 80 clinical trials sites in 16 countries on five continents. Under his leadership, the HVTN has become the model for global, collaborative research. Dr. Corey is also the principal investigator of the Fred Hutch-based operations center of the COVID-19 Prevention Network (CoVPN) and co-leads the Network’s COVID-19 vaccine testing pipeline. The CoVPN is carrying out the large Operation Warp Speed portfolio of COVID-19 vaccines and monoclonal antibodies intended to protect people from COVID-19. 

    Dr. Corey is a member of the US National Academy of Medicine and the American Academy of Arts and Sciences, and was the recipient of the Parran Award for his work in HSV-2, the American Society of Microbiology Cubist Award for his work on antivirals, and the University of Michigan Medical School Distinguished Alumnus Award. He is one of the most highly cited biomedical researchers in the last 20 years and is the author, coauthor or editor of over 1000 scientific publications. 

    Microbiology

    Retching Mice Reveal the Brain Circuit Behind Vomiting

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    ABOVE: Staphylococcus aureus © ISTOCK.COM, Artur Plawgo

    Nausea is a universally unwelcome feeling, but despite such widespread aversion, very little has been learned about the mechanism that causes an organism to vomit. That’s now changed with a report published yesterday in Cell that describes a neural pathway that purportedly controls retching in mice. The finding could lay the foundation for the development of new antinausea drugs, particularly for chemotherapy patients, according to a news release from the journal.

    When someone eats food containing certain bacteria, the microbes generate toxins that are detected by the brain. The brain then induces a variety of defensive responses designed to get the toxins out of the body. These include retching and vomiting, the study authors write, as well as feelings of nausea, which they say teaches the host to avoid the contaminated food in the future. Although these toxin responses are typically useful for survival, they are also responsible for a side effect of chemotherapy, they add. According to The New York Times, the nausea caused by chemotherapy drugs can make food unpalatable, resulting in difficulty maintaining weight. Peng Cao, a neuroethologist at Tsinghua University in Beijing and coauthor of the study, says he wanted to figure out what exactly was causing this nausea.

    “If we want to get better medications, we need to know the detailed mechanism,” he tells the Times.

    Cao and the rest of the team wanted to perform their experiment on mice, but the animals aren’t able to vomit. However, the researchers found that when mice were given staphylococcal enterotoxin A (SEA), a toxin produced by the pathogenic bacteria Staphylococcus aureus, they made facial expressions with wide and contorted mouths, and contracted their abdominal muscles in a similar way to dogs when they are about to vomit. Mice given saline solution as a control did not have the same reaction. The researchers concluded that the mice that ingested SEA were doing something akin to dry heaving or retching, which served as a proxy for vomiting in other animals.

    See “T Cells That Drive Toxic Shock in Mice Identified”

    Examining mice that had received SEA, the researchers found that the toxin induced the release of the neurotransmitter serotonin. The serotonin activated sensory neurons in the intestine, which sent signals to what is known as the dorsal vagal complex (DVC), a region in the brainstem that is thought to control digestive processes. They found that these signals primarily triggered activity in Tac-1+ neurons; when Cao and the team found a way to inactivate Tac-1+ neurons in the DVC, the mice retched significantly less.

    The scientists found that the chemotherapy drug doxorubicin also caused retching, indicating that chemotherapy drugs and bacterial toxins induce similar defensive neural responses. Moreover, when they repeated the inactivation of Tac-1+ neurons before giving mice doxorubicin, the mice once again retched less than those whose neurons were unaltered did after receiving the drug. Knowing this, and better understanding the pathways that lead to nausea and vomiting, could be an important first step in developing better antinausea drugs and improving the quality of life of chemotherapy patients, Cao tells the Times, provided the results are mirrored in humans.

    “It’s a new and exciting field of research about how the brain senses the existence of pathogens and initiates responses to get rid of them,” he says in the journal’s news release.

    See “Mopping Up Excess Chemotherapy Drugs”

    Microbiology

    Ancient viral remnants in the human genome are active in normal tissues

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    Remnants of ancient viruses in the human genome are active in healthy tissues as well as diseased ones, limiting their utility as disease biomarkers, according to a study by Aidan Burn at Tufts University in Boston, USA and colleagues, publishing October 18th in the open access journal PLOS Biology.

    Viral infection of sperm or egg cells can result in viral genes being permanently incorporated into the host genome, and the genetic remnants of ancient viruses — known as human endogenous retroviruses (HERV) — make up about 8% of the human genome. Although no longer infectious, some HERVs still contain intact genes, and the production of HERV RNA transcripts in human cells has been linked to some cancers.

    However, HERV expression in healthy tissues has been largely unexplored. To address this knowledge gap, researchers used RNA sequence data from the Genotype Tissue and Expression project to investigate the presence of transcripts belonging to a recent HERV subgroup, HML-2, in non-diseased tissues. This database includes gene expression data from 54 different tissue types collected from nearly 1000 individuals. The authors detected HML-2 transcripts in all tissue types, with elevated levels in cerebellum, pituitary, testis, and thyroid tissues.

    The results demonstrate that HML-2 activity is not limited to diseased or cancerous tissues, and this has important clinical implications. For example, the use of HML-2 expression as a cancer biomarker, or a target for therapeutics, would need to account for background expression in non-diseased tissues. More evolutionarily ancient HML-2 viruses showed the highest expression levels in human tissues, which may indicate that the activity of younger, less-degraded HERV fragments containing complete protein-coding sequences may be repressed by cells to prevent production of harmful viral proteins, the authors say.

    John Coffin, the senior author, adds, “We have found that nearly all normal human tissues express, in their RNA, one or another of about three dozen endogenous proviruses, remnants of widespread retrovirus infection of our distant ancestors. We expect this finding to provide a basis for further studies to understand the role of these elements in human biology and disease.”

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    Materials provided by PLOS. Note: Content may be edited for style and length.

    Journal Reference:

  • Aidan Burn, Farrah Roy, Michael Freeman, John M. Coffin. Widespread expression of the ancient HERV-K (HML-2) provirus group in normal human tissues. PLOS Biology, 2022; 20 (10): e3001826 DOI: 10.1371/journal.pbio.3001826

    • PLOS