Virus World

A genetically edited form of a herpes simplex virus—rewired to keep it from taking refuge in the nervous system and eluding an immune response—has outperformed a leading vaccine candidate in a new study from the University of Cincinnati, Northwestern University and the University of Nebraska-Lincoln. Published Nov. 6 in the journal Nature Vaccines, the study found that vaccinating guinea pigs with the modified live virus significantly increased the production of virus-combating antibodies. When challenged with a virulent strain of herpes simplex virus, the vaccinated animals displayed fewer genital lesions, less viral replication and less of the viral shedding that most readily spreads infection to others. The modified virus is actually a form of herpes simplex virus type 1, best known for causing cold sores around the lip. The fact that it demonstrated cross-protection against HSV type 2—the sexually transmitted type usually responsible for genital herpes—suggests that an HSV-2-specific edition of the vaccine could prove even more effective, the researchers said. The World Health Organization estimates that more than 500 million people have HSV-2, which persists for a lifetime and often flares up in response to stress. In addition to causing blisters, HSV-2 increases the risk for HIV infection and may contribute to Alzheimer's disease or other forms of dementia.

Despite the prevalence of the viruses, more than four decades of research have yet to yield an approved vaccine for HSV-1 or HSV-2. Part of the difficulty: The alphaherpesviruses, which include HSV, have evolved an especially sophisticated way of evading the immune responses aimed at destroying them.  After infecting mucosal tissues of the mouth or genitourinary tract, HSV works its way to the tips of sensory nerves that transmit signals responsible for the sensations of pain, touch and the like. With the help of a specialized molecular switch, the virus then breaks into the nerve cell, hitching a ride on the molecular equivalent of a trolley car that transports it along a nerve fiber and into the nucleus of a sensory neuron. Whereas the mucosal infection is soon cleared by the immune response, the infected neurons become a sanctuary from the body's immune system, with HSV leaving only when stirred by rises in steroids or other stress-elevated hormones in the host. Nebraska's Gary Pickard and Patricia Sollars, alongside Northwestern's Gregory Smith and Tufts University's Ekaterina Heldwein, have spent years studying how to prevent HSV from reaching the safety of the nervous system. Heldwein advanced those efforts when she characterized the architecture of a certain alphaherpesvirus protein, pUL37, that the team suspected was integral to the virus moving along nerve fibers. Computer analyses based on that architecture suggested that three regions of the protein might prove important to the process.

Smith then carefully plucked out and replaced five codons, the fundamental coding information in the DNA, from the viral genome of each region. The researchers hoped that those mutations might help impede the virus from invading the nervous system. Their hopes were rewarded when Pickard and Sollars injected mice with a virus modified in region 2, or R2, of the protein. Rather than advancing deeper into the nervous system, the virus was stuck at the nerve terminal. But the team also knew that modifying HSV could have unintended consequences. "You can keep the virus from getting into the nervous system," said Pickard, professor of veterinary medicine and biomedical sciences at Nebraska. "That's not that hard to do by making broadly debilitating mutations. But when you knock down the virus so much that it doesn't replicate well, you are not rewarded with a robust immune response that can protect you from future exposures." So the researchers were heartened when further studies showed that the R2-mutated virus performed well as a vaccine in mice. Moreover, it circumvented certain stubborn issues that have cropped up with other vaccine approaches. Some approaches have involved challenging the immune system with only a subset of HSV components, or antigens, priming the body to recognize them but potentially miss others. Some have modified the virus so that it can replicate just once, preventing long-term persistence in the nervous system but also reducing spread in mucosal tissues and, by extension, a stout immune response....

Original study published in Nature Vaccines (Nov. 6, 2020):

https://doi.org/10.1038/s41541-020-00254-8

Latent herpes virus reactivation has been documented in more than half of astronauts during space shuttle and International Space Station missions, and according to a recent study funded by NASA, the cause is stress.“Herpes virus is a broad category of viruses, beyond the small subset that cause sexually transmitted diseases.Most humans become infected early in life with one or more, and never fully clear these viruses,” Satish Mehta, PhD, senior scientist in the immunology/virology lab at the Johnson Space Center in Houston, told Infectious Disease News.

Results showed that 47 out of 89 (53%) astronauts on short space shuttle flights, and 14 out of 23 (61%) on longer space station missions shed herpes viruses in their saliva or urine samples. According to the study, astronauts shed four of the eight major human herpes viruses: Epstein-Barr, varicella-zoster and herpes simplex-1 in saliva and cytomegalovirus in urine. The researchers said most astronauts were asymptomatic, with only six developing symptoms.

“Larger quantities and increased frequencies for these viruses were found during spaceflight as compared to before or after flight samples and their matched healthy controls,” Mehta and colleagues wrote.  Mehta explained why: “[The] short answer is stress. In people with reduced immunity, such as the elderly or stressed individuals, these viruses can awaken and cause disease,” he said.

“Although NASA believes there is no clinical risk to astronauts during orbital spaceflight, there is concern that during deep space exploration missions, there may be clinical risks related to viral shedding. Although we do not have a serious clinical problem related to herpes viruses, their reactivation is an excellent ‘flag,’ or biomarker, for stress and reduced immunity.”

In the study, Mehta and colleagues noted that continued viral shedding after a flight can pose a potential risk for crew who may encounter infants, seronegative adults or immunocompromised people, so protocols have been put in place. 

The study was published in February 2019  in Frontiers in Microbiology - Virology:

https://doi.org/10.3389/fmicb.2019.00016

The herpes simplex virus, commonly known as the cold sore virus, is a devious microbe. It enters the body through regions lined with mucous membranes—mouth, nose and genitals—but quickly establishes lifelong viral hideouts inside nerve cells. After initial infection, the virus lurks dormant only to be reawakened periodically to cause outbreaks marked by the eruption of cold sores or blisters. In a handful of people, the consequences of viral re-awaking can be devastating, including blindness and brain inflammation. Antiviral medications can prevent recurrent outbreaks, but they are not always effective, so for decades, researchers have sought a solution that would quiet the virus for good. Now, using human fibroblast cells infected with herpes simplex virus (HSV), researchers at Harvard Medical School have successfully used CRISPR-Cas9 gene editing to disrupt not only actively replicating virus but also the far-harder to reach dormant pools of the virus, demonstrating a possible strategy for achieving permanent viral control. The team's findings are described Dec. 2 in eLife.

"This is an exciting first step—one that suggests it is possible to permanently silence lifelong infections—but much more work remains to be done," said study lead investigator David Knipe, the Higgins Professor of Microbiology and Molecular Genetics in the Blavatnik Institute at Harvard Medical School. Notably, the research represents the first successful instance of disrupting latent viral reservoirs through gene editing. Latent reservoirs are notoriously impervious to antiviral medications and have also proven hard to gene-edit. The experiments also identify the mechanisms by which actively replicating virus becomes uniquely vulnerable to gene editing. These very mechanisms may also explain why latent forms of the virus are less amenable to this technique.

Specifically, the experiments reveal that the DNA of an actively replicating virus is more exposed to the Cas9 enzyme—the molecular scissors in the CRISPR-Cas9 gene-editing system. This is because actively replicating viruses have fewer protective histones that wrap around their DNA to shield it. "The absence of protective histones makes the DNA more accessible and easier to cut, so it's essentially identified HSV's Achilles heel," Knipe said. The new findings offer a model system for using gene editing in a localized way to disrupt active replication in specific sites. However, Knipe cautions, the arch-challenge of delivering gene-editing therapy to neurons—where the virus hides and enters a state of dormancy—remains to be solved, Knipe added...

Published in eLife (December 2, 2019):

https://doi.org/10.7554/eLife.51662