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"We have limited funding, but we have made really good progress," Farzan said. "I'm told this is going in NIH's fast-track mechanism, so we're hoping to hear something in the not too distant future."
TIM-family Proteins Promote Infection of Multiple Enveloped Viruses through Virion-associated Phosphatidylserine
Stephanie Jemielity,
Jinyize J. Wang,
Ying Kai Chan,
Asim A. Ahmed,
Wenhui Li,
Sheena Monahan,
Xia Bu,
Michael Farzan,
Gordon J. Freeman,
Dale T. Umetsu,
Rosemarie H. DeKruyff,
Hyeryun Choe
PLOS
Published: March 28, 2013
DOI: 10.1371/journal.ppat.1003232
Abstract
Human T-cell Immunoglobulin and Mucin-domain containing proteins (TIM1, 3, and 4) specifically bind phosphatidylserine (PS). TIM1 has been proposed to serve as a cellular receptor for hepatitis A virus and Ebola virus and as an entry factor for dengue virus. Here we show that TIM1 promotes infection of retroviruses and virus-like particles (VLPs) pseudotyped with a range of viral entry proteins, in particular those from the filovirus, flavivirus, New World arenavirus and alphavirus families. TIM1 also robustly enhanced the infection of replication-competent viruses from the same families, including dengue, Tacaribe, Sindbis and Ross River viruses. All interactions between TIM1 and pseudoviruses or VLPs were PS-mediated, as demonstrated with liposome blocking and TIM1 mutagenesis experiments. In addition, other PS-binding proteins, such as Axl and TIM4, promoted infection similarly to TIM1. Finally, the blocking of PS receptors on macrophages inhibited the entry of Ebola VLPs, suggesting that PS receptors can contribute to infection in physiologically relevant cells. Notably, infection mediated by the entry proteins of Lassa fever virus, influenza A virus and SARS coronavirus was largely unaffected by TIM1 expression. Taken together our data show that TIM1 and related PS-binding proteins promote infection of diverse families of enveloped viruses, and may therefore be useful targets for broad-spectrum antiviral therapies.
Author Summary
To infect cells, enveloped viruses typically utilize cellular receptors, which mediate specific, high-affinity interactions with the viral entry protein and prime the entry protein for subsequent steps in the viral entry process. Viral entry is also enhanced by attachment factors. Although less specific than receptors, attachment factors can alter the course of infection and thus severity of viral disease by increasing the infection efficiency of specific target cells. Here we observed that TIM proteins, a group of proteins that promote phagocytosis of apoptotic cells, can dramatically enhance the entry of a number of viruses, including Ebola, West Nile and dengue viruses, whereas they have little effect on the entry of other viruses. The inability of a virus to use TIM proteins may be due to the presence of an abundant, high-affinity receptor (Lassa fever virus), or because the TIM proteins direct virions to a non-productive internalization pathway (SARS coronavirus, influenza A virus). Mechanistically, TIM proteins appear to interact with enveloped viruses and apoptotic cells similarly by binding phosphatidylserine residues exposed on the viral and cellular membranes. Collectively our studies show that TIM proteins are attachment factors that can substantially improve the infection efficiency of a number of pathogenic viruses.
http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1003232
Scripps Florida Scientist Awarded $2.3 Million to Study Dengue Fever and Related Viruses
JUPITER, FL – March 27, 2014 – The outbreak of dengue fever that infected some 20 people in Florida’s Martin County late last year unnerved many who feared the tropical disease had once again established a foothold in Florida. The last outbreaks occurred in 2009 and 2010 in Key West—before that, the disease hadn’t struck Florida in more than 70 years.
Now, scientists from the Florida campus of The Scripps Research Institute (TSRI) have been awarded $2.3 million from the National Institutes of Health to study a category of viruses that cause dengue fever, West Nile, yellow fever and other diseases spread by mosquitoes and ticks. These diseases can result in flulike symptoms, extreme pain (dengue has been called “bone-break fever”) and, in some cases, encephalitis.
This family of viruses, called “flavivirus,” affect some 2.5 billion people worldwide and cause hundreds of thousands of deaths each year. There are no antiviral treatments and a just handful of vaccines that provide protection against only a few of these diseases.
The principal investigator for the new five-year study is TSRI Associate Professor Hyeryun Choe, who will lead the effort to understand the virus’s mode of infection and how new therapies might interrupt it.
“Flavivirus uses a very clever method of infection,” Choe said. “It’s like using a side door to enter a house when the front door is locked.”
The viruses take advantage of the process that normally occurs during programmed cell death. During programmed cell death (“apoptosis”), a lipid usually found on the inner side of the cell membranes, specifically phosphatidylserine (PS), shifts to the surface, making itself readily available to any passing cellular stranger. This is where the trouble begins.
When cells are dying from a flavivirus infection, their freshly exposed PS is grabbed by the exiting virus, and phagocytes—cells that devour invading pathogens and dead and dying cells—engulf the virus as if it were a dying cell. Once engulfed by the phagocyte, the virus quickly turns the cell's own biology on its head, forcing it to produce copies of the virus.
While some viruses (influenza A for example) do not use PS in their life cycle, the flavivirus exploits this opportunity to the hilt. Infection of cells by dengue or West Nile viruses is markedly enhanced when phagocytes express receptors that recognize and bind PS.
It appears, however, that flaviviruses use only a subset of these receptors. The high selectivity, and the potency with which some of these receptors promote flavivirus infection, suggest only a small number of receptors might be effectively targeted to treat these diseases.
“We want to understand which PS receptors contribute the most to flavivirus infections and how we might block them,” Choe said. “Our studies are designed to offer insights useful in the development of new therapies.”
http://www.scripps.edu/news/press/2014/20140327choe.html
Exosomes and Their Role in the Life Cycle and Pathogenesis of RNA Viruses
Harendra Singh Chahar,1
Xiaoyong Bao,1,2 and
Antonella Casola1,2,*
Yorgo Modis, Academic Editor
1Departments of Pediatrics, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA; E-Mails: ude.bmtu@rahahcah (H.S.C.); Email: ude.bmtu@oabix (X.B.)
2Sealy Center for Vaccine Development, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA
*Author to whom correspondence should be addressed; E-Mail: ude.bmtu@alosacna; Tel.: +1-409-747-0581; Fax: +1-409-772-1761.
Recent studies on Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV), human T-cell lymphotropic virus (HTLV), and Dengue Virus (DENV) have demonstrated that exosomes released from infected cells harbor and deliver many regulatory factors including viral RNA and proteins, viral and cellular miRNA, and other host functional genetic elements to neighboring cells, helping to establish productive infections and modulating cellular responses. Exosomes can either spread or limit an infection depending on the type of pathogen and target cells, and can be exploited as candidates for development of antiviral or vaccine treatments. This review summarizes recent progress made in understanding the role of exosomes in RNA virus infections with an emphasis on their potential contribution to pathogenesis.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488737/
so Hyeryun Choe became a big PS Targeting backer back in March of 2014 and also received some money to investigate further. That is about $2.3 Million all to investigate PS = Phosphatidylserine, or shall we say flipped PS and flipped PS is "where the trouble begins"., according to Hyeryun's direct quote below.
-----------------------------------------------
Scripps Florida Scientist Awarded $2.3 Million to Study Dengue Fever and Related Viruses
March 27, 2014
JUPITER, FL – March 27, 2014 – The outbreak of dengue fever that infected some 20 people in Florida’s Martin County late last year unnerved many who feared the tropical disease had once again established a foothold in Florida. The last outbreaks occurred in 2009 and 2010 in Key West—before that, the disease hadn’t struck Florida in more than 70 years.
Now, scientists from the Florida campus of The Scripps Research Institute (TSRI) have been awarded $2.3 million from the National Institutes of Health to study a category of viruses that cause dengue fever, West Nile, yellow fever and other diseases spread by mosquitoes and ticks. These diseases can result in flulike symptoms, extreme pain (dengue has been called “bone-break fever”) and, in some cases, encephalitis.
This family of viruses, called “flavivirus,” affect some 2.5 billion people worldwide and cause hundreds of thousands of deaths each year. There are no antiviral treatments and a just handful of vaccines that provide protection against only a few of these diseases.
The principal investigator for the new five-year study is TSRI Associate Professor Hyeryun Choe, who will lead the effort to understand the virus’s mode of infection and how new therapies might interrupt it.
“Flavivirus uses a very clever method of infection,” Choe said. “It’s like using a side door to enter a house when the front door is locked.”
The viruses take advantage of the process that normally occurs during programmed cell death. During programmed cell death (“apoptosis”), a lipid usually found on the inner side of the cell membranes, specifically phosphatidylserine (PS), shifts to the surface, making itself readily available to any passing cellular stranger. This is where the trouble begins.
When cells are dying from a flavivirus infection, their freshly exposed PS is grabbed by the exiting virus, and phagocytes—cells that devour invading pathogens and dead and dying cells—engulf the virus as if it were a dying cell. Once engulfed by the phagocyte, the virus quickly turns the cell's own biology on its head, forcing it to produce copies of the virus.
While some viruses (influenza A for example) do not use PS in their life cycle, the flavivirus exploits this opportunity to the hilt. Infection of cells by dengue or West Nile viruses is markedly enhanced when phagocytes express receptors that recognize and bind PS.
It appears, however, that flaviviruses use only a subset of these receptors. The high selectivity, and the potency with which some of these receptors promote flavivirus infection, suggest only a small number of receptors might be effectively targeted to treat these diseases.
“We want to understand which PS receptors contribute the most to flavivirus infections and how we might block them,” Choe said. “Our studies are designed to offer insights useful in the development of new therapies.”
http://www.scripps.edu/news/press/2014/20140327choe.html
Scripps Florida Scientists Uncover New Facets of Zika-Related Birth Defects to Help Develop Treatment
Oct 17, 2016
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In the new study, the scientists observed the virus’s effects in animal models at two different points—during early postnatal development, when the brain is growing rapidly, and at weaning, when the brain has largely reached adult size.
“In early postnatal Zika-infected models some brain areas and cell types showed particularly large increases in apoptosis [programmed cell death] that we did not observe in older animals,” Choe said
https://www.scripps.edu/news/press/2016/20161017choe.html
Choe publicly backing PS Targeting (March 27, 2014) when state stated "This is where the trouble begins..." when PS flips to the outside of the cellular membrane. She seems to be raising the alarm "arms race" on these viruses below.
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"Scientifically, it's as good as it gets because you're married to the collaboÂrator that you trust the most," he said. "Sometimes it seeps into the marriage half of lifeâ??and sometimes work creeps too much into life. But on balance I would call it a good thing. It's no question that it helps the marriage, it strengthens it because you're with somebody who knows all aspects of you."
Having settled into a condo on the beach in Juno Beach, both are glad to be at Scripps Florida and in Florida.
They walk on the beach. Choe admits that Farzan does it more than she does and that she was a little worried about how hot it would be when they finally settled into the Sunshine State.
"I thought it would be too hot and too humid," she said, "but we adapted to it so fast and now we can't live anywhere else. It's so funny that I worried about the weather."
HIV Vaccine Demonstrates Durability Against Hard-to-Fight Strains
Publish Date:
Wednesday, July 31, 2019
An investigational vaccine successfully protected against hard-to-fight HIV strains, with long-term efficacy from a single inoculation, according to a study published in Science Translational Medicine.
The vaccine, developed by researchers at the Scripps Research Florida campus, was tested against SIVmac239, also called the â??death starâ? strain, which is known for being seemingly indestructible, according to the study. SIVmac239 is a type of simian immunodeficiency virus that replicates HIV in primates.
Different from most conventional vaccines, this vaccine uses a safe virus to fight the dangerous one, using muscle cells rather than immune cells to generate protective agents. The lab-made adeno-associated virus (AAV) carries a protective protein called eCD4-Ig, ****** which features 2 HIV co-receptors: CD4 and CCR5. ****** Once injected into the muscle, the vaccine causes muscle cells to produce this protective protein, which prevents HIV from being able to infect.
â??We have solved 2 problems that have plagued HIV vaccine studies to dateâ??namely, the absence of duration of response and the absence of breadth of response,â? lead author Michael Farzan, PhD, said in a press release. â??No other vaccine, antibody, or biologic protects against the 2 viruses for which we have demonstrated robust protection.â?
For the study, the researchers tested the ability of eCD4-Ig to prevent SIVmac239 infection in macaques, administering eCD4-Ig to primates with the AAV before repeated escalated doses of the infection. Overall, the findings showed that the vaccine offered complete protection from high-dose SIVmac239 challenges that infected all 8 of the research animals. However, the study showed that animals could eventually become infected when exposed to atypically large loads of HIV, and that the virus is also capable of developing resistance to eCD4-Ig.
Subsequent analysis showed viral loads in the treated group were lower and eCD4-Ig put selective pressure on SIV, according to the study.
â??The results of our paper are encouraging for the potential of AAV as a platform for prevention of disease generally, and in concert with eCD4 as an agent for stopping HIV infection,â? Dr Farzan concluded. â??We hope ultimately to prove that our approach is safe for both infected and at-risk persons at a cost that makes it useable everywhere.â?
References
Farzan M,
Gardner MR,
Fellinger CH, et al.
AAV-delivered eCD$-Ig protects rhesus macaques from high-dose SIVmac239 challenges. Science Translational Medicine. 2019. DOI: 10.1126/scitranslmed.aau5409
https://www.specialtypharmacytimes.com/news/hiv-vaccine-demonstrates-durability-against-hard-to-fight-strains
Fusion Stage of HIV-1 Entry Depends on Virus- Induced Cell Surface Exposure of Phosphatidylserine
Page 1 of 33
Highlights
-HIV-cell binding triggers phosphatidylserine (PS) exposure at the cell surface
-PS exposure depends on gp120-coreceptor interactions, Ca2+ signaling, and TMEM16F
-Suppression of PS exposure inhibits Env restructuring, viral fusion, and infection
-PS signaling, a hallmark of activation, facilitates HIV entry
Elena Zaitseva,1
Eugene Zaitsev,1
Kamran Melikov,1
Anush Arakelyan,2
Mariana Marin,3
Rafael Villasmil,4
Leonid B. Margolis,2
Gregory B. Melikyan,3 and
Leonid V. Chernomordik1,5,*
1Section on Membrane Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
2Section on Intercellular Interactions, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
3Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
4Flow Cytometry Core, National Eye Institute, National Institutes of Health, Bethesda, MD, USA
5Lead Contact
*Correspondence: chernoml@mail.nih.gov
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https://www.cell.com/cell-host-microbe/pdfExtended/S1931-3128(17)30252-4
