While SARS-CoV-2 continues to dominate our news and daily lives, research on other important viruses continues unabated in research labs around the world. An important recent paper in Nature Communications used multiple approaches to decode the genome of herpes simplex virus type 1 (HSV-1). HSV-1 causes oral lesions commonly known as “cold sores” or “fever blisters”. (HSV-1 can sometimes cause genital lesions though herpes simplex type 2 is more often the cause of genital infections.) HSV-1 is spread by direct person-to-person contact, for example by kissing. Viruses transmitted by the donor will infect skin cells in the oral region of the recipient. In some recipients, painful blisters develop that ultimately open into virus-filled ulcers that last 5-10 days before healing. However, many newly infected individuals have very mild infections and don’t develop lesions so they never know they were infected. Nonetheless, everyone who is infected remains infected for the rest of their lives. After replicating in the skin cells, the virus enters the adjacent nerve cells and hides there in an inactive or latent state. The virus persists indefinitely in the nerve cells and causes no harm, but under certain conditions may reactivate. Things such as sunlight, hormonal changes, and stress can cause reactivation in some people. If reactivated, the virus travels back down the nerve cell and reinfects the skin in the same location as the original infection giving rising to the painful lesion again. Consequently, people prone to reactivation have their lesions returning repeatedly to the same location. Unfortunately, whether on an initial infection or a reactivation infection, infectious virus is present in and on the skin several days before the lesion appears. The presence of the virus makes these individuals infectious and since they lack symptoms they can unknowingly pass the virus on to other people. This often silent spread facilitates transmission leading to estimates that roughly 70% of the adult population worldwide is infected with HSV-1.
In addition to the painful skin lesions, HSV-1 is capable of causing more severe and life-threatening infections. For example, infection of the eye (herpes keratitis) can occur if a patient touches their lesion, picks up virus on their finger, and then rubs their eye. If not treated HSV-1 eye infections can lead to permanent damage and even blindness. Even more serious outcomes can develop if HSV-1 reaches the brain (herpes encephalitis). This may occur through viruses in the nerve cells traveling directly to the brain or possibly viruses in the bloodstream reaching the brain. In either case, HSV-1 encephalitis is an extremely dangerous illness with a fatality rate of 70-80% in untreated cases. It often presents as a vague, flu-like illness with headache, fever, and drowsiness then progresses to confusion, dementia, and seizures. Newborns and very young children are highly susceptible to HSV-1 infection which can lead to generalized infection often with brain involvement. As in adults, brain infections in children have a high mortality rate and can cause permanent brain damage in survivors. Fortunately, there is an excellent antiviral drug for herpes simplex virus, acyclovir. Acyclovir and its derivatives can be very effective at stopping the virus and have low toxicity. Unfortunately, acyclovir needs to be given early in infection to be effective and there are now acyclovir-resistant strains of HSV-1 in circulation so new anti-HSV-1 drugs are needed. Typically, antiviral drugs attack critical viral proteins to inhibit viral reproduction, so knowing the complete array of viral proteins (the viral proteome) that can be targeted for drug development is important. The Nature Communications paper is an important advance because it provides a greatly expanded identification of potential HSV-1 proteins.
You might think that identifying all the proteins a virus makes would be as simple as looking at the sequenced genome and picking out the genes that can encode proteins. This approach does easily find large potential protein-coding regions called open reading frames (ORFs), and 80 such large ORFs in the HSV-1 genome have been known for decades and do encode proteins. However, it is often unclear whether or not small ORFs actually encode proteins or are just unused segments of the DNA. In addition, viruses often use multiple genetic schemes to pack as much protein-coding potential into their genomes as possible. To use a linguistics analogy, the large ORFs are like a base word such as the word “form”. But the virus may use tricks to add protein-coding information to either end of the base ORF just as prefixes and suffixes can be added to words. So “form” can become “deform” or “formal” and these longer words have very different meanings than the base word. Likewise, coding extensions on either end of the base ORF can generate new ORFs whose protein function is quite different from the base ORF protein. Using sophisticated experimental and computational approaches the authors of this study confirmed the existence of 284 HSV-1 ORFs, including 46 new large ORFs and 134 small ORFs, greatly expanding the list of HSV-1 proteins. While the functions of these newly predicted viral proteins are unknown, this study provides many new potential targets for therapeutic attack. Hopefully among this large cadre of new viral proteins are vulnerable ones whose function can be easily inhibited to provide the next generation of anti-HSV-1 drugs for clinical use.