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Viruses are parasites. The only way they can grow is by hijacking their hosts. When they infect a human host, viruses use human proteins to multiply and modify the human cells to sustain the infection. At the same time, the human host activates defense mechanisms to fight the infection.

Most current drugs against viral infections target the virus itself. But scientists are interested in developing therapies that aim for host proteins instead, or the genes that produce them, in part because such therapies are believed less likely to elicit drug resistance. A detailed understanding of virus-host interactions is crucial to the success of this strategy.

A team of Gladstone Institutes scientists led by Senior Investigator Nevan Krogan, PhD, has been cataloging host proteins that physically bind to virus proteins. These physical interactions identify human proteins that the virus can use to infect cells and propagate. However, they don't reveal how host proteins work together to facilitate infection.

To address this gap, Krogan and staff scientist David Gordon, PhD, with colleagues at UC San Francisco (UCSF), University College Dublin, and the Mount Sinai School of Medicine, have developed a new way to understand how host cells control HIV infection in human cells.

Their approach entails disrupting host genes rather than proteins. It is based on the idea, pioneered by Krogan, that you obtain richer information about the functions of genes–and the proteins they encode–when you disable the genes in pairs, instead of one by one. In a paper published in Molecular Cell, the team describes a map of the genes controlling HIV infection in human cells, which they built by assessing more than 63,000 combinations of human genes associated with HIV infection.

HIV is a major public health concern, with an estimated 36.7 million people living with chronic infection, and over 20.9 million people receiving continuous treatment. Studying the impact of gene disruptions in pairs rather than one by one yields important information on how genes work together to mediate virus infection, highlighting processes we can target with drugs to inhibit infection."

Nevan Krogan, Ph.D., senior investigator, professor of Cellular and Molecular Pharmacology at UCSF, and the director of the UCSF Quantitative Biosciences Institute

The map, which the team refers to as a viral epistasis map (vE-MAP), is an essential advance for HIV research in several other ways. For one thing, it uncovers a previously unsuspected set of genes required for the growth of the virus in human cells. For another, the vE-MAP can be used to analyze how different HIV mutants affect host cells or to test drugs that disrupt HIV-host interactions.

Strength in numbers

The vE-MAP is an adaptation of the E-MAP, which Krogan and his colleagues pioneered and refined over the past 15 years to identify genes that control how cells grow. At the core of this approach is the Krogan lab's ability to disrupt a large number of genes, test them in pairs, and analyze the results via sophisticated computational methods.

"The principle behind E-MAPs is that when you disrupt two genes at once and examine the impact on a cell, you sometimes see effects that are significantly larger or smaller than you would have predicted from the effect of disrupting either gene alone," said Krogan.

These unexpected effects suggest that the functions of the two genes are related. Moreover, by carrying out these pairwise disruptions across hundreds of genes, scientists can find groups of genes with similar patterns of interactions, a sign that they are likely to take part in the same molecular process.

"And so, instead of finding important genes one at a time, you can all at once identify multiple, distinct networks of genes affecting the process you are studying," said Gordon.

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The E-MAP approach has mostly been used to study cell growth. Gordon, in collaboration with a student from University College Dublin, Ariane Watson, had to modify it to study virus infection. The most tricky part was to implement a sophisticated data acquisition and scoring system, which allowed them to measure HIV infection accurately across hundreds of thousands of samples, and compare the effect of pairwise and single-gene disruptions.

It would be an overwhelming effort to test all combinations of the over 20,000 protein-coding genes in the human genome. Instead, the scientists focused on genes already suspected to influence HIV biology. In particular, they used the genes encoding a large number of human proteins that the Krogan lab had previously found to bind to HIV proteins. In all, they included over 350 genes in their analysis and tested over 63,000 pairwise disruptions.

New players at the HIV-host interface

Although HIV is one of the best-studied human viruses and is now well-controlled by antiretroviral therapy, there is no cure for HIV/AIDS. Moreover, antiretroviral therapy is costly, which can make it impractical in resource-poor countries. The search for new means of halting or eradicating the virus is, therefore, still a priority.

Among the genes that stood out in the vE-MAP were several members of the CNOT family, whose role in HIV biology had never before been established. The authors demonstrated that the CNOT complex promotes HIV infection by suppressing innate immunity in CD4+ T cells, the type of immune cells that HIV preferentially targets in humans. Innate immunity is a defense mechanism by which host cells can fight infection.

"The impact of CNOT on innate immunity is a key, yet previously unrecognized, host pathway critical to HIV infection. It will serve as a potential novel therapeutic target in future studies," said Krogan.

For instance, scientists can now study if targeting the CNOT complex with drugs could be a way to help HIV patients fight the infection more effectively.

Furthermore, the vE-MAP uncovered genes that had little impact when disrupted individually, but a great effect when tested together.

"These genes would be overlooked in classic, single-gene disruption experiments," said Gordon. "They confirm the potential of the vE-MAP to uncover new mechanisms by which HIV interacts with human cells."

Combining drugs that target two of these genes at the same time might thus be a promising therapeutic strategy, especially for a virus such as HIV/AIDS, which has evolved multiple ways of tapping its hosts' resources.

The vE-MAP was also able to pick up genes that specifically interact with a known HIV mutant. This observation bodes well for the ability of the vE-MAP to identify distinct host factors affecting the various forms of HIV, or the virus mutants that arise in response to currently available drugs.

Additional testing with a drug known to interfere with HIV-associated human proteins gives the authors confidence that their vE-MAP approach could, in the future, be used to screen for novel anti-HIV drugs and to understand their mode of action.

"This vE-MAP provides an unprecedented view of how HIV hijacks and rewires the cellular machinery in human cells during infection," said Krogan. "It will generate many new ideas and avenues to identify and test novel therapies."

And the benefits may not be limited to HIV research.

"Our work is proof-of-principle that the vE-MAP approach is a powerful way to map out the interface between HIV and human cells, and to uncover new therapeutic avenues," said Gordon. "We now look forward to testing it on other pathogens."

Source:

Gladstone Institutes

A new study published in February 2020 in the journal JAMA Otolaryngology-Head and Neck Surgery shows that using mainstream media to depict rare diseases in a realistic manner can prompt greater public awareness and support for such conditions.

Rare diseases have a very small presence in this world, affecting about 400 million people around the globe. Despite the very few cases of each kind of disease, they often cause a lot of suffering and require significant treatment and rehabilitation. In other words, they create a heavy burden in financial terms as well as the amount of care they need, both on the patients and the health care system. Yet it is challenging to mobilize funds for research, prevention, and treatment, to raise awareness about the condition, or to get sufficient manpower.

Increasing the level of awareness is an urgent necessity, therefore. One possible way out is to show television shows focusing on these conditions as part of widely seen programs. One is the Netflix series, Stranger Things, which showcases the life of Dustin Henderson, a fictional individual born with the rare disease cleidocranial dysplasia (CCD). Henderson is portrayed by actor Gaten Matarazzo III who himself has this condition.

LOS ANGELES – JUN 28: Cast at the "Stranger Things" Season 3 World Premiere at the Santa Monica High School on June 28, 2019 in Santa Monica, CA. Image Credit: Kathy Hutchins / Shutterstock

CCD is a genetic condition in which the clavicles, or collar bones, and the teeth fail to grow or grow abnormally. These features are emphasized in scenes where Dustin is explaining the condition to his friends and colleagues.

However, symptoms vary between patients, even in the same family. CCD currently affects 1 in a million children the world over, both boys and girls.

The early features of abnormal bone development include a prolonged period of open fontanelles when the bones of the skull remain separate at the front and back of the head for more than the usual length of time. The absence of complete collarbones may make the chest appear narrow, and the shoulders are sloping. In fact, many of these children can make their shoulders touch in front.

Bone density is low, the pelvis is narrow, and the height shorter than expected. Baby teeth are lost early, and the secondary teeth arrive late, which may cause the jaw to be crowded with teeth and the jaw misaligned.

The disease is due to an abnormality of the RUNX2 gene, mostly due to a de novo mutation, that is, one which arises at random in the developing embryo rather than being inherited from the parents. If one of the two copies of this gene is affected, the condition will manifest itself.

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Treatment could include dental replacements, speech therapy, treatment of sinus and ear infections, supplementation with vitamin D and calcium, and protecting the head from trauma until the bones are fused.

The study

The current study uses Google Trends and data from websites related to CCD to examine the link between how the condition is portrayed on television shows and the resulting increase in public interest and awareness of CCD.

Google Trends was used to look at the trends for searches focusing on CCD after the show Stranger Things was released. The researchers did a worldwide search for searches with this keyword, over a 5-year period from 2014 to 2019. Also, they asked several foundations dealing with CCD, such as the Children’s Craniofacial Foundation, about any increase in the number of calls or website hits after each season’s release of Stranger Things. This was compared with the expected traffic.

The findings

The researchers found that search interest surged by over 94% after the third season’s release of Stranger Things. In comparison, an increase of about 11% and almost 13% was seen after season 1 and season 2.

Public interest in CCD was reported to increase by all websites related to this topic. However, quantifiable data were obtained only from the foundation About KidsHealth, which had, on average, 5 to 80 views of the CCD page each week, but in the week succeeding the third season’s release of the show, 10,000 visits.

Implications

The portrayal of the condition on the popular television show has helped spark interest in many individuals. Each season has seen a spurt in weekly searches above the predicted number. Meanwhile, Matarazzo has participated in setting up the new foundation CCD Smiles, which is focused on raising awareness of this condition around the world, helping affected people with their dental work, and helping research.

The importance of harnessing celebrity power is vast reach it can offer via already existing links to the public and the media.

And when public awareness increases, funding goes up, early diagnosis is more likely, treatment becomes more broad-based, and people learn to understand and cope with the disorder. This, in turn, helps those affected by it to develop more coping strategies, feel a greater sense of integration into the broader community, and have a better quality of life.

The media also has a catalytic role in helping hundreds of thousands of people to understand such conditions better and to make sure they are correctly represented. Accurate artistic depiction of such conditions is guided by the Entertainment Industries Council, which develops material to help writers and producers understand the disease better so they can present it correctly.

However, at present, there is no guide material for CCD and many other rare diseases. Therefore, the study concludes, “Although writers need to exercise caution when portraying characters with rare disorders, the inclusion of such characters in the mainstream media may be a beneficial strategy to raise awareness of them.”

Journal reference:

Johnson AL, Torgerson T, Cooper C, Khojasteh J, Vassar M. Public Awareness of Cleidocranial Dysplasia After Season Releases of Stranger Things. JAMA Otolaryngol Head Neck Surg. Published online February 20, 2020. doi:10.1001/jamaoto.2019.4791