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Unusual case of father-to-son HIV transmission reported. Diagnosis of HIV-1 infection in the 4-year old child of an HIV-negative mother led to a forensic analysis to determine the source of the infection and try to date the transmission of the virus. The results of genetic, phylogenetic, and serologic data analysis on both the father and son and the hypothesis for how the boy became infected are published in a study in AIDS Research and Human Retroviruses, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers.

Based on comparative analysis of genetic, phylogenetic, and serologic data from the father and the son, the researchers concluded that the virus was accidentally transmitted to the son during the first days of the child’s life. During this time of seroconversion, the father was being treated for infection with varicella-zooster virus (chicken pox) and syphilis when he developed large vesicles all over his body that profusely leaked fluids. The high virus production early in HIV infection would have made the fluids leaking from the father’s skin blisters highly infectious. These infectious fluids could have come in contact with the newborn child causing this atypical HIV transmission.

“Although this type of father-to-son HIV transmission event is rare, it is important that the general public realize that HIV is present in most bodily fluids and can be transmitted in atypical and unexpected ways,” says Thomas Hope, PhD, Editor-in-Chief of AIDS Research and Human Retroviruses and Professor of Cell and Molecular Biology at Northwestern University, Feinberg School of Medicine in Chicago, IL. “In this case, the circumstances of fluids leaking from skin blisters with the high amount of HIV present in the first months of HIV infection led to the unfortunate infection of a newborn child.”

Infectious disease

World’s first human case of rat disease discovered. For the first time, a case of rat hepatitis E has been discovered in a human in Hong Kong. A 56-year-old man has been diagnosed with the disease, researchers from the University of Hong Kong said. It was not previously known the disease could be passed from rats to humans.

“Previous lab experiments have found that rat hepatitis E virus cannot be transmitted to monkeys, and human hepatitis A virus cannot be transmitted to rats,” said Dr. Siddharth Sridhar, clinical assistant professor at the University of Hong Kong, explaining that monkeys are very close to humans when it comes to disease susceptibility. The risk of rat hepatitis E affecting humans has been underestimated.

The man developed the disease after undergoing a liver transplant following chronic infection with hepatitis B. He continued to show signs of abnormal liver function, with no obvious cause. Investigations revealed signs of an immune response to hepatitis E, which is a major cause of viral hepatitis in humans all around the world. But tests for the human form of the virus came back negative. Genetic sequencing of the virus infecting the man then revealed similarities with the rat form of the disease and the man was given antiviral treatment.

The team then wanted to know how the disease was able to cross over from rats into a human and believe the man caught the disease from rats infesting a garbage chute near his home. The team believes the most important control measure would be to limit the rat population and ensure there is no garbage for rats to feed on.

The Hong Kong patient’s immune system was compromised, given he had recently undergone a liver transplant, putting him at higher risk of contracting infections.

As most people would not look for this particular virus, “we don’t have standard tests yet,” he added. “This example of it actually occurring means that we probably should start looking more for it, especially in immunocompromised people,” said Hibberd. “The virus seems to be relatively diverse which suggests that it’s existed a long time.”

Hepatitis causes inflammation of the liver, with various viruses that cause it. Most commonly, hepatitis A, B, and C spread through either contaminated food and water or blood and other body fluids, depending on the virus. The human form of hepatitis E is typically transmitted through contaminated water, and is estimated to infect 20 million people worldwide, resulting in 3.3 million people showing symptoms each year. According to the WHO, it caused approximately 44,000 deaths in 2015, making up 3.3 percent of all deaths from viral hepatitis.

The animal form of the disease is thought to infect wild boars, domestic pigs and deer, as well as rats and other rodents.

Artificial intelligence

Harnessing AI to improve drug combination design and personalized medicine. A new auto-commentary published in SLAS Technology looks at how an emerging area of artificial intelligence (AI), specifically the analysis of small systems-of-interest specific datasets, can be used to improve drug development and personalized medicine. The auto-commentary builds on a study recently published by the authors in Science Translational Medicine about an AI platform, Quadratic Phenotypic Optimization Platform (QPOP), that substantially improves combination therapy in bortezomib-resistant multiple myeloma to identify the best drug combinations for individual multiple myeloma patients.

It is now evident that complex diseases, such as cancer, often require effective drug combinations to make any significant therapeutic impact. As the drugs in these combination therapies become increasingly specific to molecular targets, designing effective drug combinations as well as choosing the right drug combination for the right patient becomes more difficult.

AI is having a positive impact on drug development and personalized medicine. With the ability to efficiently analyze small datasets that focus on the specific disease of interest, QPOP and other small dataset-based AI platforms can rationally design optimal drug combinations that are effective and based on real experimental data and not mechanistic assumptions or predictive modeling. Furthermore, because of the efficiency of the platform, QPOP can also be applied toward precious patient samples to help optimize and personalize
combination therapy.

Flavivirus

CRISPR screen identifies gene that helps cells resist West Nile virus. UT Southwestern researchers report the use of CRISPR genome-wide screening to identify a gene that helps cells resist flavivirus infection, including West Nile virus, dengue fever, Zika virus, and yellow fever.

In a study published in Nature Microbiology, the team led by Dr. John Schoggins, Assistant Professor of Microbiology, used the cutting-edge CRISPR technology to identify the IFI6 gene as a potent antiviral gene targeting flaviviruses. The researchers then used traditional cell culture studies to confirm the gene’s role in protecting against infection by Zika, West Nile, dengue, and yellow fever viruses.

“Other studies have used CRISPR genetic screens to identify cellular genes that are required for flavivirus infection. Our study is the first to use this technology to identify cellular genes that inhibit infection,” said Dr. Schoggins, a Nancy Cain and Jeffrey A. Marcus Scholar in Medical Research, in Honor of Dr. Bill S. Vowell, and a Clayton Foundation Investigator.

“In mammals, cells naturally defend against viral infection through interferon, a molecule that sets off a warning system that a virus has been detected and that the cells need to engage their viral defense systems. The cells do this by activating hundreds of interferon-stimulated genes,” he said. “Flaviviruses cause substantial human disease, and interferon is involved in the body’s innate immune response to these viruses.”

The research team used recently developed genome-wide CRISPR screening technology to identify which of the interferon-induced genes played a major role in suppressing flavivirus infection. He praised the work of graduate student and lead author Blake Richardson and of co-author Dr. Maikke Ohlson, a senior research scientist in his laboratory. “Blake performed all the phenotypic and mechanistic work on how IFI6inhibits flaviviruses and Dr. Ohlson performed the CRISPR screen that allowed us to uncover IFI6 as a potent suppressor of flavivirus infection,” he said.

“In the CRISPR screen, we used human liver cells and knocked out every gene in the genome – about 19,000 genes – one at a time. We then stimulated the cells with interferon, knowing that this stimulation would normally allow the cells to resist viral infection. For the cells that did not resist infection – because they were missing a gene due to the CRISPR knockout – we used next-generation sequencing to figure out the identity of the relevant genes,” he said.

Schoggins explained that the CRISPR gene-editing technology made the study extremely efficient, uncovering the prominent flavivirus-inhibiting role of IFI6.

“The brilliance of the technology is that all of these CRISPR-targeted cells are pooled together in just a few big cell culture dishes. The cells are also bar-coded so you know which gene is missing from each cell when you observe how they respond to the addition of interferon,” he said.

In cell culture studies, the IFI6 gene – apparently working via its protein product, also called IFI6 – inhibited yellow fever, a flavivirus known to infect the liver. Cells with a working IFI6 gene also inhibited dengue, Zika, and West Nile. The researchers confirmed those results in liver cells by repeating the experiment in kidney and skin cell lines and in neurons.

Future work entails drilling down into the molecular mechanism of the IFI6 protein, with the hope that this knowledge may provide a foundation for developing therapies that could target flavivirus infection.

Sporadic West Nile cases have been reported this summer in the United States.

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