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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Researchers from Fred Hutchinson Cancer Center in Seattle, Scripps Research in La Jolla, California, IAVI and other collaborating institutions have characterized robust T-cell responses in volunteers participating in the IAVI G001 Phase 1 clinical trial to test the safety and immune response of a self-assembling nanoparticle HIV vaccine.
Their work, published in Science Translational Medicine, signals a major step toward development of a vaccine approach to end the HIV/AIDS epidemic worldwide. The antigen used in this study was jointly developed by IAVI and Scripps Research and has been shown in previous analyses to stimulate VRC01-class B cells, an immune response considered promising enough for boosting in further studies.
We were quite impressed that this vaccine candidate produced such a vigorous T-cell response in almost all trial participants who received the vaccine. These results highlight the potential of this HIV-1 nanoparticle vaccine approach to induce the critical T-cell help needed for maturing antibodies toward the pathway of broadly neutralizing against HIV.”
Julie McElrath, MD, PhD, senior vice president and director of Fred Hutch’s Vaccine and Infectious Disease Division and co-senior author of the study
However, she added, this is the first step, and heterologous booster vaccines will still be needed to eventually produce VRC01-class broadly neutralizing antibodies, which in previous studies have demonstrated the ability to neutralize approximately 90% of HIV strains.
“We showed previously that this vaccine induced the desired B-cell responses from HIV broadly neutralizing antibody precursors. Here we demonstrated strong CD4 T-cell responses, and we went beyond what is normally done by drilling down to identify the T cell epitopes and found several broadly immunogenic epitopes that might be useful for developing boosters and for other vaccines,” William Schief, PhD, executive director of vaccine design for IAVI’s Neutralizing Antibody Center at Scripps Research and professor, Department of Immunology and Microbiology, at Scripps Research, who is co-senior author of the study.
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The trial is a phase 1, randomized, double-blind and placebo-controlled study to evaluate the safety and effectiveness of a nanoparticle HIV vaccine in healthy adult volunteers without HIV. It was comprised of two groups with 18 vaccine and six placebo recipients per group, with 48 total enrollees. Participants were given two doses of the vaccine or placebo eight weeks apart.
McElrath acknowledged the groundbreaking work of her lab team, the biostatistical team and Fred Hutch’s Vaccine Trials Unit for their invaluable contributions to the study. The Vaccine Trials Unit conducts multiple vaccine trials and was one of only two sites for this study.
Findings from the study include:
Vaccine-specific CD4 T cells were induced in almost all vaccine recipients.
Lymph node GC T follicular helper cells increased after vaccination compared to placebo.
Lumazine synthase protein, needed for self-assembly of the particle, also induced T-cell responses that can provide additional help to ultimately enhance efficacy in a sequential vaccine strategy.
Vaccine-specific CD4 T cells were polyfunctional and had diverse phenotypes.
LumSyn-specific CD8 T cells were highly polyfunctional and had a predominantly effector memory phenotype.
CD4 T-cell responses were driven by immunodominant epitopes with diverse and promiscuous HLA restriction.
CD8 T-cell responses to LumSyn were driven by HLA-A*02-restricted immunodominant epitopes B- and T-cell responses correlated within but not between LN and peripheral blood compartments.
This study was funded by the Bill & Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery; IAVI Neutralizing Antibody Center; National Institute of Allergy and Infectious Diseases; and Ragon Institute of MGH, MIT and Harvard.
Study authors WRS and SM are inventors on a patent filed by Scripps and IAVI on the eOD-GT8 monomer and 60-mer immunogens (patent number 11248027, “Engineered outer domain (eOD) of HIV gp 120 and mutants thereof”). WRS, KWC and MJM are inventors on patents filed by Scripps, IAVI and Fred Hutch on immunodominant peptides from LumSyn (Title: Immunogenic compositions; filing no. 63127975).
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Cohen, K. W., et al. (2023) A first-in-human germline-targeting HIV nanoparticle vaccine induced broad and publicly targeted helper T cell responses. Science Translational Medicine.doi.org/10.1126/scitranslmed.adf3309.
Genetic alterations that give rise to a rare, fatal disorder known as MOGS-CDG paradoxically also protect cells against infection by viruses. Now, scientists at the Lewis Katz School of Medicine at Temple University have harnessed this unusual protective ability in a novel gene-editing strategy aimed at eliminating HIV-1 infection with no adverse effects on cell mortality.
The new approach, described online April 28 in the journal Molecular Therapy – Nucleic Acids, is based on a combination of two gene-editing constructs, one that targets HIV-1 DNA and one that targets a gene called MOGS – defects in which cause MOGS-CDG. In cells from persons infected with HIV-1, the Temple researchers show that disrupting the virus’s DNA while also deliberately altering MOGS blocks the production of infectious HIV-1 particles. The discovery opens up new avenues in the development of a cure for HIV/AIDS.
Proper MOGS function is essential for glycosylation, a process by which some cellular proteins synthesized in the body are modified to make them stable and functional. Glycosylation, however, is leveraged by certain kinds of infectious viruses. In particular, viruses like HIV, influenza, SARS-CoV-2, and hepatitis C, which are surrounded by a viral envelope, rely on glycosylated proteins to enter host cells.
In the new study, lead investigators Kamel Khalili, PhD, Laura H. Carnell Professor and Chair of the Department of Microbiology, Immunology, and Inflammation, Director of the Center for Neurovirology and Gene Editing, and Director of the Comprehensive NeuroAIDS Center at the Lewis Katz School of Medicine, and Rafal Kaminski, PhD, Assistant Professor at the Center for Neurovirology and Gene Editing at the Lewis Katz School of Medicine designed a genetic approach to exclusively turn on CRISPR to impede MOGS gene expression through DNA editing within immune cells that harbor replication competent, HIV-1. Their novel approach is expected to avoid any impact on the health of uninfected cells that retain normal MOGS gene function. Stimulation of the apparatus in HIV-1 infected cells disrupted the glycan structure of the HIV-1 envelope protein, culminating in the production of non-infectious virus particles.
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“This approach is conceptually very interesting,” said Dr. Khalili, who is also senior investigator on the new study. “By mitigating the ability of the virus to enter cells, which requires glycosylation, MOGS may offer another target, in addition to the integrated viral DNA for developing the next generation of CRISPR gene-editing technology for HIV elimination.”
Dr. Kaminski, Dr. Khalili, and Tricia H. Burdo, PhD, Professor and Vice Chair in the Department of Microbiology, Immunology, and Inflammation and the Center for Neurovirology and Gene Editing at Temple and an expert in the use of non-human primate models for HIV-1, have been working together to further assess the efficacy and safety of CRISPR-MOGS strategy in preclinical studies. In previous work, the team demonstrated that CRISPR-based technology can successfully remove viral DNA from the cells of infected non-human primates.
Other researchers who contributed to the study include Hong Liu, Chen Chen, Shuren Liao, and Shohreh Amini, Department of Microbiology, Immunology, and Inflammation, Center for Neurovirology and Gene Editing, Lewis Katz School of Medicine at Temple University; Danielle K. Sohaii, Conrad R.Y. Cruz, and Catherine M. Bollard, Center for Cancer and Immunology Research, Children’s National Health System, The George Washington University; Thomas J. Cradick and Jennifer Gordon, Excision Biotherapeutics, San Francisco, CA; Anand Mehta, Stephane Grauzam, and James Dressman, Department of Cell and Molecular Pharmacology, Medical University of South Carolina; and Carlos Barrero and Magda Florez, Department of Pharmaceutical Sciences, School of Pharmacy, Temple University.
The research was supported in part by grants from the National Institutes of Health and the W.W. Smith Charitable Trust.
Liu, H., et al. (2023) Strategic Self-Limiting Production of Infectious HIV Particles by CRISPR in Permissive Cells. Molecular Therapy — Nucleic Acids.doi.org/10.1016/j.omtn.2023.04.027.
An international study coordinated by the MELIS-UPF researchers Andreas Meyerhans and Juana Díez has identified Schlafen 12, a new HIV restriction factor that could pave the way for new strategies for curing the infection.
Researchers have identified a novel HIV restriction factor, Schlafen 12 (SLFN 12), which disrupts viral protein production and helps virus-infected cells evade treatment. This discovery could lead to improved therapeutic strategies for curing HIV infections by targeting and eliminating latently infected cells.
An international study led by MELIS-UPF researchers from the Infection Biology and Molecular Virology laboratories has identified and characterized Schlafen 12 (SLFN 12) as a novel HIV restriction factor. SLFN 12 shuts down viral protein production and helps virus-infected cells to escape from anti-HIV therapy and immune responses. These findings pave the way for improving therapeutic strategies that aim to cure HIV infections.
Human Immunodeficiency Virus (HIV) infections, if left untreated, lead to the gradual destruction of the immune system, AIDS, in its final stages. Worldwide, some 650,000 individuals die of AIDS each year, making it a major threat to human health. Nonetheless, despite there being no general cure for an established infection, appropriate antiretroviral therapy enables people living with HIV to lead a relatively healthy life. Unfortunately, once treatment is stopped, the virus returns from a reservoir of latently infected cells.
“Latency is a major barrier impairing virus elimination in HIV-infected individuals. We will not be able to cure an existing infection until we will get rid of latently infected cells. This is why it is essential to understand how latency works,” explains Andreas Meyerhans, ICREA research professor at UPF who has coordinated the study together with Juana Díez.
The paper, published today (May 10) in the journal Communication Biology, has identified and characterized SLFN12, a protein that restricts the production of viral proteins by cleaving specific cellular tRNAs, the building blocks for protein construction. As a consequence, in the presence of active SLFN12, HIV-infected CD4 T cells are not able to complete the virus production process but keep its templates, HIV RNA, in a latent state.
“SLFN12 impairs protein production, restricting the production of viral particles. Such cells are latently infected, invisible to the immune system and anti-HIV therapies,” says Mie Kobayashi-Ishihara, first author of the manuscript.
The study also reveals how SLFN12 can specifically inhibit HIV protein production without blocking cellular protein production. “SLFN12 cleaves Leucine-UUA tRNA, a building block that is rarely used for cellular proteins but essential for HIV viral proteins,” Juana Díez explains.
This finding opens the possibility to design new therapeutic strategies against HIV. “Blocking SLFN12 antiviral functions should increase viral protein expression and thus, enable the host immune system and antiviral drugs to better eliminate viral reservoirs. Once you start producing the virus, it becomes visible again. You get your target back. So, you can attack it, and hopefully, definitely eliminate the latent infected cells,” concludes Meyerhans.
Reference: “Schlafen 12 restricts HIV-1 latency reversal by a codon-usage dependent post-transcriptional block in CD4+ T cells” by Kobayashi-Ishihara, M at al., 10 May 2023, Communication Biology. DOI: 10.1038/s42003-023-04841-y
Funding: Takeda Science Foundation, JSPS Oversea Research Fellowship, MINECO, FEDER, Miguel Servet program by ISCIII, Horizon 2020 Framework Programme, NIH/National Institutes of Health, Spanish Ministry of Science and Innovation, “María de Maeztu” Programme for Units of Excellence in R&D, ISCIII/MINECO and FEDER
Researchers from Temple University and UNMC collaborate in a study recently published in the journal Proceedings of the National Academy of Sciences.
Gene-editing therapy targeting both HIV-1, the virus responsible for AIDS, and CCR5, the co-receptor assisting viral entry into cells, has been demonstrated to effectively eradicate HIV infection, according to new research from the Lewis Katz School of Medicine at Temple University and the University of Nebraska Medical Center (UNMC). This study, published in the journal Proceedings of the National Academy of Sciences (PNAS), marks the first instance of combining a dual gene-editing approach with antiretroviral medications to successfully cure animals of HIV-1.
“The idea to bring together the excision of HIV-1 DNA with inactivation of CCR5 using gene-editing technology builds on observations from reported cures in human HIV patients,” said Kamel Khalili, Ph.D., Laura H. Carnell Professor and Chair of the Department of Microbiology, Immunology, and Inflammation, Director of the Center for Neurovirology and Gene Editing, and Director of the Comprehensive NeuroAIDS Center at the Lewis Katz School of Medicine. “In the few instances of HIV cures in humans, the patients underwent bone marrow transplantation for leukemia, and the donor cells that were used carried inactivating CCR5 mutations.”
Dr. Khalili and Howard E. Gendelman, MD, Professor and Chair of the Department of Pharmacology and Experiential Neuroscience at UNMC, were senior investigators on the new study. The two researchers have been long-time collaborators and have strategically combined their research strengths to find a cure for HIV.
“We are true partners, and what we achieved here is really spectacular,” Dr. Gendelman said. “Dr. Khalili’s team generated the essential gene-editing constructs, and we then applied those constructs in our LASER-ART mouse model at Nebraska, figuring out when to administer gene-editing therapy and carrying out analyses to maximize HIV-1 excision, CCR5 inactivation, and suppression of viral growth.”
In previous work, Drs. Khalili and Gendelman and their respective teams showed that HIV can be edited out from the genomes of live, humanized HIV-infected mice, leading to a cure in some animals. For that research, Dr. Khalili and co-investigator, Rafal Kaminski, Ph.D., Assistant Professor at the Center for Neurovirology and Gene Editing at the Katz School of Medicine, combined their expertise in CRISPR gene-editing technology for targeting HIV-1 with a therapeutic strategy known as long-acting slow-effective release (LASER) antiretroviral therapy (ART) that was co-developed by Dr. Gendelman and Benson Edagwa, Ph.D., Assistant Professor of Pharmacology at UNMC. LASER ART holds HIV replication at low levels for long periods of time, decreasing the frequency of ART administration.
Despite being able to eliminate HIV in LASER-ART mice, the researchers found that HIV could eventually re-emerge from tissue reservoirs and cause rebound infection. This effect is similar to rebound infection in human patients who have been taking ART but suddenly stop or experience a disruption in treatment. HIV integrates its DNA into the genome of host cells, it can lie dormant in tissue reservoirs for long periods of time, out of reach of antiretroviral drugs. As a consequence, when ART is stopped, HIV replication renews, giving rise to AIDS.
To prevent rebound infection, Dr. Khalili and colleagues began work on next-generation CRISPR technology for HIV excision, developing a new, dual system aimed at permanently eliminating HIV from the animal model. “From success stories of human HIV patients who have undergone bone marrow transplantation for leukemia and been cured of HIV, our hypothesis was that the loss of the virus’s receptor, CCR5, is important to permanently eliminating HIV infection,” he explained. They developed a simple and more practical procedure for the inactivation of CCR5 that includes an IV inoculation of the CRISPR gene editing molecule.
Experiments in humanized LASER-ART mice carried out by Dr. Gendelman’s team showed that the constructs developed at Temple, when administered together, resulted in viral suppression, restoration of human T-cells, and elimination of replicating HIV-1 in 58 percent of infected animals. The findings support the idea that CCR5 has a key role in facilitating HIV infection.
The Temple team also anticipates soon testing the dual gene-editing strategy in non-human primates. To do so, Dr. Khalili will collaborate with Tricia H. Burdo, Ph.D., Professor and Vice Chair in the Department of Microbiology, Immunology, and Inflammation at the Katz School of Medicine, a known expert in the use of non-human primate models for studying HIV-1, who was also a co-author on the new study. Dr. Burdo and her team are interested in understanding the involvement of CCR5 in SIV-infected primates. Her laboratory previously played a key part in research demonstrating the effectiveness and safety of CRISPR-based technology in removing HIV DNA from primate cells.
The new dual CRISPR gene-editing strategy holds exceptional promise for treating HIV in humans. “It is a simple and relatively inexpensive approach,” Dr. Khalili noted. “The type of bone marrow transplant that has brought about cures in humans is reserved for patients who also have leukemia. It requires multiple rounds of radiation and is not applicable in resource-limited regions, where HIV infection tends to be most common.”
“Curing HIV is the big picture,” Dr. Gendelman added. “Through our ongoing collaboration, Temple and UNMC have carried out meaningful research that could ultimately impact the lives of many people.”
Reference: “CRISPR editing of CCR5 and HIV-1 facilitates viral elimination in antiretroviral drug-suppressed virus-infected humanized mice” by Prasanta K. Dash, Chen Chen, Rafal Kaminski, Hang Su, Pietro Mancuso, Brady Sillman, Chen Zhang, Shuren Liao, Sruthi Sravanam, Hong Liu, Emiko Waight, Lili Guo, Saumi Mathews, Rahsan Sariyer, R. Lee Mosley, Larisa Y. Poluektova, Maurizio Caocci, Shohreh Amini, Santhi Gorantla, Tricia H. Burdo, Benson Edagwa, Howard E. Gendelman and Kamel Khalili, 1 May 2023, Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.2217887120
The study was funded by the National Institutes of Health.
Disclosures: Kamel Khalili is Co-Founder and Chief Scientific Consultant and holds equity in Excision BioTherapeutics, which has licensed the viral gene-editing technology from Temple University. Kamel Khalili and Rafal Kaminski are named inventors on patents that cover the viral gene-editing technology. Tricia Burdo serves on the Scientific Advisory Board and holds equity in Excision BioTherapeutics. These named researchers are employed by Temple University and conduct research activities sponsored by the company.
Drs. Howard Gendelman and Benson Edagwa are Co-Founders and Scientific Consultants in Exavir Therapeutics, which has licensed the ultra-long acting prodrug technology from the University of Nebraska Medical Center. Drs. Gendelman and Edagwa are named inventors on patents that cover the LASER ART technology. Drs. Khalili and Gendelman have not received financial compensation from any other third parties for any aspects of this published work.
In addition to owning the viral gene-editing technology that Excision is licensing, Temple University also holds an equity interest in Excision. As a result of these interests, Temple University could ultimately potentially benefit financially from the outcome of this research. In addition to having an ownership interest in the long-acting antiretroviral technology that Exavir has licensed, UNMC’s technology transfer organization, UNeMed, also holds an equity interest in Exavir. As a result of these interests, UNMC could potentially benefit financially from the outcome of this research.
In a recent article published in the Lancet journal, researchers quantified the global bacterial antimicrobial resistance (AMR) burden to present deaths and disability-adjusted life-years (DALYs) attributable to and associated with 23 pathogens, 12 major infectious syndromes, 18 drug categories, and 88 pathogen–drug combinations.
They considered two counterfactual scenarios and used consistent methods to arrive at the study estimates as they had no clue of the extent to which susceptible or no infection would replace drug-resistant infections in a scenario when there was no drug resistance.
Bacterial AMR, an emerging public health threat, is making antibiotic use futile or less effective against many common bacterial diseases affecting animals and humans. A United Kingdom (UK) government-commissioned review of AMR stated that it could claim 10 million lives annually by 2050.
The World Health Organization (WHO) and numerous other researchers have also raised that AMR spread is a pressing issue that needs immediate attention; if left unaddressed, rising AMR will make several bacterial pathogens highly fatal in the near future. The challenge is to gather current data on pathogen–drug combinations contributing to actual bacterial AMR burden for all world regions, even those with minimal surveillance.
According to the authors, studies have only reported AMR-related data for specific regions and a limited number of pathogens and pathogen–drug combinations. For instance, the United States Centers for Disease Control and Prevention (US-CDC) published a report in 2019 on AMR-related deaths for 18 AMR-related threats using surveillance data.
Similarly, Cassini et al. estimated the burden of eight and 16 pathogens and pathogen–drug combinations, respectively, for the European region between 2007 and 2015. Despite the significant contributions made by these studies to the field of AMR, there is a lack of comprehensive global estimates covering all locations, all pathogens, and all pathogen–drug combinations contributing to the rising burden of bacterial AMR.
Key Takeaways
First comprehensive assessment of the global burden of antimicrobial resistance (AMR) for bacterial infections.
Estimated 4.95 million deaths associated with bacterial AMR in 2019, including 1.27 million deaths attributable to bacterial AMR.
Lower respiratory infections accounted for the most deaths associated with resistance in 2019.
Six leading pathogens for deaths associated with resistance.
One pathogen-drug combination, meticillin-resistant S aureus, caused more than 100,000 deaths attributable to AMR in 2019.
Burden of AMR is highest in low-resource settings, particularly in western sub-Saharan Africa.
Serious data gaps in many low-income settings
About the study
In the present study, researchers used predictive statistical modeling to generate global estimates of bacterial AMR burden for all world locations, covering 204 countries for which they used all available data from the Global Burden of Diseases (GBD), Injuries, and Risk Factors study. The GBD study collated age- and gender-specific estimates for 369 injuries and illnesses in 204 nations and territories between 1990 and 2019.
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They retrieved data from published scientific literature, multisite research collaborations, clinical trials, research institutes based in low-income and middle-income countries (LMICs), public and private hospital records, diagnostic testing data, surveillance systems of pharmaceutical companies, global, national, and enhanced surveillance systems, and other relevant sources, encompassing 471 million (MN) patient records or isolates and 7,585 study-location years, which they gathered using varied strategies and used for study estimations.
The researchers modeled deaths and DALYs for 204 countries and territories to present cumulative estimates of AMR burden globally and for 21 GBD regions, including seven GBD super-regions.
For the first counterfactual scenario, where susceptible infections substituted all drug-resistant infections, they estimated only deaths and DALYs directly due to AMR. For the second counterfactual scenario, where no infection substituted all drug-resistant infections, they estimated all deaths and DALYs related to resistant infections. Both estimates had different utilities; however, both could inform the development of intermediation strategies to regulate AMR spread.
The study approach comprised ten estimation steps within five all-encompassing modeling components, each with varied data requirements; consequently, input data for each modeling component also varied.
Study findings
Substituting drug-resistant infections by no infections (first counterfactual scenario) and susceptible infections (second counterfactual scenario) would have saved 4.95MN and 1.27MN deaths, respectively, in 2019, implying that in 2019, the global AMR burden related to drug-resistant infections for 88 pathogen–drug combinations was ~4.95MN deaths (95% UI), of which drug resistance alone caused 1.27MN deaths. Moreover, after ischaemic heart disease and stroke, AMR accounted for most deaths in 2019.
Additionally, the study analysis revealed that AMR-related all-age death rates were highest in some LMICs, as opposed to the common notion that the burden of bacterial AMR would be higher in high-resource settings with higher antibiotic consumption. Indeed, AMR is emerging as a more serious problem for some of the world’s poorest countries. The authors noted the highest AMR-related death rates in sub-Saharan Africa and South Asia as a function of the prevalence of resistance and critical lower respiratory, bloodstream, and intra-abdominal infections, in these regions.
The study also highlighted that in LMICs, there are other drivers of the higher AMR burden, like a scarcity of laboratory infrastructure for microbiological testing needed to narrow antibiotic use or make it more targeted. Among other factors, counterfeit antibiotics, poor sanitation and hygiene, poor regulations on antibiotics use, etc., also drive resistance.
Further, the researchers identified six pathogens, E. coli, K. pneumoniae, S. pneumoniae, A. baumannii, S. aureus, and P. aeruginosa, who contributed most to the burden of AMR in 2019; they accounted for 73.4% (95% uncertainty interval) of deaths attributable to bacterial AMR. WHO has recognized all six as priority pathogens; however, except S. pneumoniae, targeted primarily through pneumococcal vaccination, none is the focus of global health intervention programs.
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Seven pathogen–drug combinations caused more than 50000 deaths, highlighting the need for expanding infection prevention and control (IPC) policies targeting the deadliest combinations, bolstering vaccine and antibiotic development, and improving access to essential second-line antibiotics where needed. Furthermore, resistance to β-lactam antibiotics, e.g., penicillins and cephalosporins, and fluoroquinolones accounted for >70% of deaths attributable to AMR across pathogens. These antibiotics are the first line of empirical treatment for severe infections.
In 2017, the WHO published a priority list to inform research priorities related to new antibiotics for pathogens with multidrug resistance that caused deadly infections. However, this list covered only five of the seven pathogen–drug combinations estimated to have caused the most deaths in 2019; for instance, this list did not feature fluoroquinolone-resistant E. coli and meticillin-resistant S. aureus only as a “high” but not a “critical” priority.
Per study estimates, the magnitude of bacterial AMR as a global public health issue is as much as human immunodeficiency virus (HIV) and malaria, perhaps, much higher. Additionally, the AMR pattern varied with geographical location, pathogens, and pathogen–drug combinations. Thus, the regional estimates made in this study could help tailor local responses as the ‘One Size Fits All’ approach might not be appropriate.
Despite concerted data collection efforts, high-quality data on AMR was sparsely available for many LMICs. Nevertheless, an improved scientific understanding of this rapidly emerging health threat should be the highest priority for global health policymakers.
Conclusions
The present study used major methodological innovations, two varying AMR counterfactual scenarios, and comprehensive data to fetch novel insights into the global AMR burden. Most importantly, it incorporated models tested and iterated over years during GBD study analysis. So, when used collectively, these models provided a complete estimate of AMR burden with robust geographical coverage.
Further, the researchers compared findings with other causes of death, offering much-needed context on the scale of the burden of this rapidly growing public health problem. The study analysis confirmed that bacterial AMR posed the biggest threat to human health in sub-Saharan Africa and South Asia, involved a diverse set of pathogens, and is exceptionally high for multiple essential antibiotic classes, including β-lactams and fluoroquinolones.
Furthermore, efforts to build and enhance laboratory infrastructure and bolster national & global AMR plans of action are essential to addressing the universal AMR burden. Future studies should also evaluate the indirect effects of AMR, such as its effect on the prophylaxis of infections in organ transplant recipients.
In the future, the study estimates could inform treatment guidelines against many predominant bacterial pathogens for a given infectious syndrome, which, along with estimates of pathogen–drug burden, could inform their treatment guidelines customized for a specific location.
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In their quest to create treatments that could potentially eliminate HIV infection completely, scientists have been searching for all the locations where the virus can conceal its genetic material. In a recent study, a team of scientists from Johns Hopkins Medicine used blood samples from individuals with HIV on long-term suppressive therapy and discovered new evidence that HIV genomes can persist in a stable reservoir within circulating white blood cells known as monocytes.
Monocytes are a type of circulating immune cell with a short lifespan, that eventually develop into macrophages. Macrophages are immune cells capable of engulfing and destroying foreign elements such as viruses, bacteria, and other cells that do not belong in the host organism.
In the current research, published March 27 in Nature Microbiology, the scientists found evidence that blood samples from people with HIV undergoing long-term, standard antiretroviral therapy contained monocytes that harbor stable HIV DNA capable of infecting neighboring cells.
The scientists say the findings may provide a new direction for efforts to improve therapies and eventually cure HIV, which affects more than 34 million people worldwide, according to the World Health Organization. Current antiretroviral drugs can successfully suppress HIV to nearly undetectable levels but have not resulted in the total eradication of the virus.
“We don’t know how critical these monocytes and macrophages are to eradication of HIV, but our results suggest we should continue research efforts to understand their role in this disease,” says Janice Clements, Ph.D., professor of molecular and comparative pathobiology at the Johns Hopkins University School of Medicine.
Scientists have long known that HIV stashes its genome most often in a type of immune cell called a CD4+ T-cell. These hiding places are known as reservoirs.
“To eradicate HIV, the goal is to find biomarkers for cells that harbor the HIV genome and eliminate those cells,” says Rebecca Veenhuis, Ph.D., assistant professor of molecular and comparative pathobiology at the Johns Hopkins University School of Medicine.
To further study the role of monocytes and macrophages in circulating blood as HIV reservoirs, the Johns Hopkins-led team of scientists obtained blood samples between 2018 and 2022 from 10 men with HIV, all of them taking long-term, standard antiretroviral medications.
The researchers extracted blood cells from the samples and grew the cells in the laboratory. Typically, monocytes transform very quickly — within about three days — into macrophages, producing monocyte-derived macrophages.
All 10 men had detectable HIV DNA in their monocytes-turned-macrophages but at levels 10 times lower than those found in the men’s CD4+ T cells, the well-established HIV reservoir.
For the next phase of the research, to determine if HIV genomes were present in monocytes prior to macrophage differentiation, the team used an experimental assay to detect intact HIV genomes in monocytes. The assay was based on one that fellow Johns Hopkins scientist Robert Siliciano, M.D., Ph.D., developed in 2019 to detect the HIV genome in CD4+ T cells.
The scientists, including research associate Celina Abreu, Ph.D., used the assay on blood samples taken from another group of 30 people (eight men from the first group and 22 female participants) with HIV, also treated with standard antiretroviral therapy. The researchers found HIV DNA in the CD4+ T cells and in the monocytes of all 30 participants.
The scientists were also able to isolate HIV produced by infected monocytes from half of the research participants. The virus extracted from these cells was able to infect CD4+ T cells.
Three of the participants had their blood examined several times over the four-year study period, and each time, the scientists found HIV DNA and infectious virus produced by their monocyte-derived macrophages. “These results suggest that monocytes may be a stable reservoir of HIV,” says Clements.
In further research, the Johns Hopkins research team plans to pinpoint the subset of monocytes found to harbor HIV DNA and the source of these infected cells.
Reference: “Monocyte-derived macrophages contain persistent latent HIV reservoirs” by Rebecca T. Veenhuis, Celina M. Abreu, Pedro A. G. Costa, Edna A. Ferreira, Janaysha Ratliff, Lily Pohlenz, Erin N. Shirk, Leah H. Rubin, Joel N. Blankson, Lucio Gama, and Janice E. Clements, 27 March 2023, Nature Microbiology. DOI: 10.1038/s41564-023-01349-3
The study was funded by the National Institutes of Health, the Johns Hopkins University National Institute of Mental Health Center for Novel Therapeutics for HIV-associated Cognitive Disorders, and the Johns Hopkins University Center for AIDS Research, an NIH-funded program.
Targeted testing for HIV in emergency departments has great potential for increasing diagnoses, this year’s European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) in Copenhagen, Denmark, (15-18 April), will hear.
An analysis of data from 34 emergency departments (ED) in Spain found that the number of HIV diagnoses more than trebled after targeted testing was implemented.
Researcher Dr Juan González del Castillo, head of the Infectious Disease Group of Spanish Emergency Medicine Society (SEMES), says: “Early diagnosis is key to avoiding the spread of HIV infection and improving patients’ prognosis but rates of undiagnosed and late-diagnosed infections are still high.
“An estimated 20% of infected people globally do not know they are living with HIV and late diagnosis rates are close to 50% in the developed world. In Spain, the figure is 48%.
“Screening for HIV in hospital emergency departments could increase the number of diagnoses, as well as allow more cases to be detected earlier.”
Guidance released by SEMES in 2021recommends the promotion of HIV testing and referral to appropriate specialists for follow-up in individuals attending emergency departments (ED) for treatment related to one of six conditions or behaviours: sexually transmitted infections (STI), mononucleosic syndrome (MN), herpes zoster virus (HZ), community-acquired pneumonia (CAP), practice of chemsex (CS) and HIV post-exposure prophylaxis (PEP). These are common in people with HIV and are also frequently seen in ED.
In this longitudinal study, Dr González del Castillo, head of the emergency department at Hospital Clínico San Carlos, Madrid, Spain, and colleagues used administrative data and medical charts from 34 Spanish EDs (13% of the national network) participating in the Dejatuhuella (Leave your mark) programme to evaluate levels of HIV testing before (July-Dec 2019) and after (Jan to June 2022) the SEMES guidance was implemented.
The number of HIV tests ordered in ED increased from 7,080 to 13,436. This represents an increase of 75%, when differences in the number of people attending ED are taken into account.
The number of HIV diagnoses increased more than three-fold, from 65 to 224. This represents an increase of 220%, when ED attendance figures are factored in.
The positive test rate increased from 0.92% to 1.67%. This was expected, as previous studies had shown a high positive rate in the six conditions and behaviors covered by the SEMES recommendations.
There was a significant increase in HIV testing in all of the recommended areas, apart from practice of chemsex. STI (36% of patients tested for HIV before implementation vs. 67% after implementation), MS (27% vs. 51%), CAP (7% vs. 21%), HZ (6% vs. 29%), PEP (68% vs 83%). The rate of HIV in CS remained unchanged at 78%.
The demographic and health characteristics of the individuals diagnosed in both periods were similar.
There was a significant reduction in the time between ED attendance and the first appointment with an HIV specialist (median of 30 days vs. 7 days), as well as the initiation of antiviral treatment (median of 24 days vs.14 days).
The study’s authors conclude that the implementation of targeted testing for HIV in emergency departments led to a significant increase in HIV diagnoses.
To date, a total of 103 EDs have implemented the recommendations. Data from SEMES shows that in 2021 and 2022, 113,030 tests were performed, with 287 HIV diagnoses in 2021 and 601 in 2022 –888 new diagnoses in these two years.3 (It isn’t possible to make comparison with earlier years.)
If it is assumed that one diagnosis prevents another two to four cases, the new diagnoses in these two years will have led to 1,756 to 3,512 new cases being avoided.
Dr González del Castillo says: “We really hope that the Dejatuhuella programme will reverse the downward trend in HIV diagnoses in Spain and reduce the spread of HIV and the high rates of late diagnosis.
“EDs could play a crucial role in HIV diagnosis. We know from previous research that one in three missed opportunities to diagnose HIV occurs in ED and we also know that for many people, their ED is their only point of contact with the healthcare system.
“Increasing the rates of diagnosis and early diagnosis doesn’t just have hugeimplications for individuals’ health and public health, it would also be cost-effective.
“A recent economic assessment of the SEMES strategy calculated that it would prevent 13,615 new infections and have potential savings for the healthcare system of €4,411 million in two decades, with an economic return of €224 per euro invested.”
Targeted screening is one of the two main methods of HIV screening in ED; the other is opt-out screening.
A project in the England is using opt-out HIV testing in A&Es in areas with the highest prevalence of HIV. All adults who are having blood tests while in A&E are tested for HIV unless they opt out. In many areas, hepatitis B and hepatitis C are also tested for.
Data from the 28 A&Es participating in the first 100 days of the project (April to July 2022) shows that more than 250,000 HIV tests were carried out. There were 128 HIV diagnoses, 325 hepatitis B diagnoses and 153 hepatitis C diagnoses.
“It would be difficult to implement a universal testing strategy like this in Spain, where explicit consent for HIV testing is required,” says Dr González del Castillo. “In addition, some ED physicians may be reluctant to order tests that will not help them diagnose and treat the condition that patient has presented with.
“Targeted HIV screening in the ED, as we are doing in Spain, can be impactful, more cost-effective, and better accepted by both patients and physicians than universal testing.
“On the other hand, we are working on recommendations for hepatitis B and C testing and many EDs have already started doing it at the same time as HIV, with 63 new hepatitis C diagnosis in 2021 and 2022.”
He concludes: “The role that ED can play in HIV detection is pivotal and must be recognised and promoted, whatever the strategy and wherever people are in the world.”
A systematic review and meta-analysis published in the Clinical Microbiology and Infection Journal highlights the protective effect of male circumcision on the prevalence, incidence, and clearance of human papillomavirus (HPV) infection in males and their female sexual partners.
Human papillomavirus (HPV) is the most common sexually transmitted infection globally. While low-risk HPV types are associated with genital warts, high-risk HPV types are considered major causative factors for cervical cancer.
Male circumcision is known to have protective effects against many sexually transmitted infections and sexual activity-related conditions.
Many studies have found a link between male circumcision and reduced risk of human immunodeficiency virus (HIV) infection, herpes simplex virus type 2 infection, syphilis, genital ulcer, chancroid, and candidiasis.
In this systematic review, scientists have provided a detailed overview of the association between male circumcision and the risk of HPV infection in males and their female sexual partners. The review also explores whether the protective effects of circumcision vary between different penile sites.
Study design
The scientists searched various scientific documentation databases and included observational and experimental studies reporting the effect of male circumcision on the prevalence, incidence, and clearance of HPV infection in males and their female sexual partners.
Regarding study definitions, prevalence refers to the presence of an HPV infection at any timepoints; incidence refers to the presence of an HPV infection absent at a previous time point; and clearance refers to the absence of a previously-present HPV infection.
For the risk of bias assessment, the Newcastle-Ottawa scale and the Cochrane risk-of-bias tool were used for observational studies and randomized trials, respectively.
Important observations
The initial screening of databases led to the identification of 1,409 studies, of which 32 studies, including 25 unique study populations, were finally included in the systematic review and meta-analysis. These studies were published between 2002 and 2022.
Among selected studies, 17 were cross-sectional, ten compared two groups cross-sectionally, and five were randomized clinical trials.
In these studies, samples for HPV infection detection and genotyping were collected from different sites in males, including the urethra, foreskin, glans and/or corona, shaft, scrotum, and perianal area. In females, the samples were taken from the cervix and vagina.
Prevalence of HPV infection
The prevalence of HPV infection among all participants at baseline ranged from 8.7% to 69.8%. 21 studies reported the association between circumcision and HPV infection prevalence in males.
According to the study estimates, circumcision significantly reduced the risk of HPV infections at both glans and shaft. The highest protective effect of circumcision was observed at the glans, irrespective of the viral types (low-risk and high-risk HPV types).
Incidence of HPV infection
The association between circumcision and HPV infection incidence in males was reported by nine studies. Similar to the prevalence findings, circumcision significantly reduced the risk of incident HPV infection at the glans. This association remained unchanged when stratified by low-risk and high-risk HPV types.
Clearance of HPV infection
The association between circumcision and HPV infection clearance in males was reported by seven studies.
In these studies, circumcision significantly increased both the rate and risk of HPV infection clearance at the glans. This occurred irrespective of the types of HPV (low-risk or high-risk).
HPV infection outcomes in females
A total of six studies investigated the association between male circumcision and HPV infection outcomes in female partners of circumcised males. In these studies, circumcision significantly reduced the risk of prevalent high-risk HPV infections and the incidence rate of high-risk HPV infections in female partners.
A similar but non-significant trend was also reported for prevalent infections and the incidence rate of low-risk HPV infections.
Significance
This systematic review and meta-analysis indicate that male circumcision has significant protective effects against the prevalence, incidence, and clearance of HPV infections at the glans penis.
Circumcision also protects female partners of circumcised males against contracting HPV infection.
As mentioned in the article, circumcision is believed to protect against sexually transmitted infections by changing keratinization and the local immune environment of the penis.
The current systematic review suggests that male circumcision might act as a potential preventive intervention, especially in regions where HPV-related cancers are highly prevalent, and anti-HPV vaccination is not available.
To develop treatments that may one day entirely rid the body of HIV infection, scientists have long sought to identify all of the places that the virus can hide its genetic code. Now, in a study using blood samples from men and women with HIV on long-term suppressive therapy, a team led by Johns Hopkins Medicine scientists reports new evidence that one such stable reservoir of HIV genomes can be found in circulating white blood cells called monocytes.
Monocytes are short-lived circulating immune cells that are a precursor to macrophages, immune cells able to engulf and destroy viruses, bacteria and other cells foreign to the host.
In the current research, published March 27 in Nature Microbiology, the scientists found evidence that blood samples from people with HIV undergoing long term, standard antiretroviral therapy contained monocytes that harbor stable HIV DNA capable of infecting neighboring cells.
The scientists say the findings may provide a new direction for efforts to improve therapies and eventually cure HIV, which affects more than 34 million people worldwide, according to the World Health Organization. Current antiretroviral drugs can successfully suppress HIV to nearly undetectable levels, but have not resulted in total eradication of the virus.
We don’t know how critical these monocytes and macrophages are to eradication of HIV, but our results suggest we should continue research efforts to understand their role in this disease.”
Janice Clements, Ph.D., professor of molecular and comparative pathobiology, Johns Hopkins University School of Medicine
Scientists have long known that HIV stashes its genome most often in a type of immune cell called a CD4+ T-cell. These hiding places are known as reservoirs.
“To eradicate HIV, the goal is to find biomarkers for cells that harbor the HIV genome and eliminate those cells,” says Rebecca Veenhuis, Ph.D., assistant professor of molecular and comparative pathobiology at the Johns Hopkins University School of Medicine.
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To further study the role of monocytes and macrophages in circulating blood as HIV reservoirs, the Johns Hopkins-led team of scientists obtained blood samples between 2018 and 2022 from 10 men with HIV, all of them taking long-term, standard antiretroviral medications.
The researchers extracted blood cells from the samples and grew the cells in the laboratory. Typically, monocytes transform very quickly -; within about three days -; into macrophages, producing monocyte-derived macrophages.
All 10 men had detectable HIV DNA in their monocytes-turned-macrophages, but at levels 10 times lower than those found in the men’s CD4+ T cells, the well-established HIV reservoir.
For the next phase of the research, to determine if HIV genomes were present in monocytes prior to macrophage differentiation, the team used an experimental assay to detect intact HIV genomes in monocytes. The assay was based on one that fellow Johns Hopkins scientist Robert Siliciano, M.D., Ph.D., developed in 2019 to detect the HIV genome in CD4+ T cells.
The scientists, including research associate Celina Abreu, Ph.D., used the assay on blood samples taken from another group of 30 people (eight men from the first group and 22 female participants) with HIV, also treated with standard antiretroviral therapy. The researchers found HIV DNA in the CD4+ T cells and in monocytes of all 30 participants.
The scientists were also able to isolate HIV produced by infected monocytes from half of the research participants. The virus extracted from these cells was able to infect CD4+ T cells.
Three of the participants had their blood examined several times over the four-year study period, and each time, the scientists found HIV DNA and infectious virus produced by their monocyte-derived macrophages. “These results suggest that monocytes may be a stable reservoir of HIV,” says Clements.
In further research, the Johns Hopkins research team plans to pinpoint the subset of monocytes found to harbor HIV DNA and the source of these infected cells.
