The complex truth behind the herpes simplex virus

Dr Sherin (Left) and Dr Navneet Singh in the lab.

It’s likely you have heard of herpes, the notorious viral infection that causes cold sores around our mouths or even in less desirable regions.

These seemingly straightforward symptoms, however, barely scratch the surface of the complex nature of the pathogen, Herpes Simplex Virus (HSV), and its impact on our lives.

With infected individuals being asymptomatic and oblivious to their condition, most herpes cases go unnoticed. This lack of visible symptoms makes it alarmingly easy for the virus to spread. In fact, studies suggest that up to 80% of Australians carry HSV-1, the most common strain of the Herpesvirus.

Also astonishing is that an effective cure for this seemingly “simple” virus remains elusive. Despite being heavily studied by scientists, the more we delve into the realm of HSV research, the clearer it becomes that HSV is far from simplistic.

Simply complicated

Five years ago, Professor David Tscharke’s Viruses and Immunity Lab welcomed two bright and eager researchers, Navneet and Sherin, both determined to uncover new avenues for treating HSV infections.

At first glance, one may question the severity of herpes since most people emerge unscathed after being infected. However, the truth is that herpes can lead to devastating consequences.

Herpes keratitis, a corneal infection, for instance, stands as one of the leading causes of infectious blindness. Moreover, neonatal herpes and herpes-related encephalitis, which involves inflammation of the brain, result in death for a staggering 70% of affected infants.

“These diseases may not be widespread, but there are individuals who suffer greatly due to HSV,” Navneet acknowledges.

“It’s the severity combined with the frequency of the disease that makes it an important pathogen to study,” Sherin adds.

Yet, finding an Achilles heel for this virus proves to be no mean feat.

For one thing, depending on the type of host cell they infect, HSV has the ability to produce either lytic infection, which involves the active replication of its viral genome, or latent infections, when the virus remains inactive in the infected cells.

“Current therapies primarily target the active or replicating phase of the virus, neglecting the latent phase,” Navneet explains, “Because once HSV enters latency, it becomes completely silent, making it nearly impossible to identify targetable changes at the cellular level.”

The challenge intensifies due to the fact that in latency, the virus resides specifically in neurons, which complicates potential treatment strategies even more.

“Neurons are immune privileged—the body will be reluctant to target neurons as they cannot be regenerated,” Navneet reveals. “Thus, targeting HSV within neurons becomes exceedingly difficult, as we cannot risk damaging or killing these vital cells.”

With latency established, the virus can periodically reactivate to cause recurrent disease.

Adding to the myriad of difficulties is the virus’s adeptness at evading the immune system.

“HSV has beautifully co-evolved with humans,” Sherin states, highlighting the virus's remarkable ability to hide from our immune surveillance.

With latent infections and immune evasion tactics, HSV poses a profound challenge that demands the young researchers’ unwavering attention and dedication.

Rise to the challenge

“In the start it was very difficult,” recounts Sherin, who came from a microbiology background and didn’t know much about immunology.

“Luckily, we have members in the lab who are always supportive,” says Navneet, who, like Sherin, is an international student uprooting a new life to an unfamiliar country. “And they became our closest friends,” Sherin echoes.

Benefiting from the supportive research environment, Sherin and Navneet have made significant strides in their respective projects amidst all the challenges and intricacies.

Navneet's focus lies in unravelling the factors that control latency within infected host cells. His investigations into microRNAs, which regulate gene expression, have revealed that inhibiting the production of a specific protein crucial for processing precursor miRNA can destabilise the latent virus.

"We observed a loss in the HSV genome, and the stability of the viral genome during latency was compromised," Navneet explains.

This finding could lead to the identification of therapeutic targets against the latent phase of HSV infection, opening brand-new possibilities for herpes treatment.

On the other hand, Sherin delved into HSV's evasive tactics, primarily through its utilisation of a protein called Infected Cell Protein (ICP)47. The protein renders the infected cell unable to signal CD8+ T cells, immune cells responsible for clearing the virus, about the infection, and thus allows the virus to hide from the immune system.

“During my PhD, I have looked at how herpes-infected cells interact with CD8+ T cells.”

However, Sherin faced a unique challenge situated in a key aspect of her research: the animal model.

Unlike humans, mice are not the natural host for the virus, and as a result, HSV does not hide from the mouse immune system as effectively as it does in humans—the intricate co-evolution history simply doesn’t exist between HSV and mice.

This posed a significant obstacle when using mouse models for preclinical research, as extrapolating the data from mice to humans was always uncertain.

To address this challenge, Sherin’s lab developed a 'humanised' mouse model, which sought to mimic the behaviour of the virus in infected humans.

This innovative approach aimed to provide a better animal model for preclinical HSV research. Using animal models that are more reliable in resembling the human scenario, researchers can map out the interactions between infected cells and immune cells more accurately and propel the development of immunotherapy.

One small step at a time

After years of tireless pursuit, Navneet and Sherin have recently passed their PhDs, leaving an indelible mark on their endeavour to understand HSV.

Nevertheless, they humbly acknowledge the slow pace of progress in the overall field of herpes research.

“There is still so much more to uncover about herpes,” Dr Navneet asserts.

Dr Sherin concurs, highlighting the complex consequences of interactions between HSV and its human host that have yet to be fully comprehended.

Undoubtedly, there lies a long and challenging road ahead. The intricate pathways and proteins influenced by HSV represent only the tip of the iceberg in our understanding. Yet, the purpose of research lies in continuously pushing the boundaries of knowledge and making incremental progress, even if the landscape of the field evolves slowly.

“Just keep going,” Sherin advises, drawing strength from personal experience. “Sometimes, it feels daunting when nothing seems to work. But if you persist, you will discover that perseverance pays off.”