Herpes simplex virus (HSV) flies under a false flag. There’s little about its mayhem, wreaked on the human body, that’s simple. Virtually every man, woman and child on earth harbors HSV, as evidenced by 90 percent of the planet’s population carrying herpes antibodies in its blood.

The virus comes in two persuasions, types 1 and 2, which, respectively, inflict the quiet pandemics of oral and genital infection. In the U.S. alone, 22 percent of the population is infected with HSV-2, and 1.6 million new genital herpes infections are predicted to occur annually.

HSV’s police blotter starts with cold sores or fever blisters (Herpes labialis), which come on suddenly and disappear in seven to 10 days or so. What triggers these itchy, burning facial lesions is a mystery as old, perhaps, as Homo sapiens. Guesswork over the years has nominated sunburn, urinary and gastrointestinal tract infection, fever, emotional stress and anxiety.

More severe and more discomfiting are highly contagious itching, burning attacks on the male and female genitalia (caused by Herpes genitalis), which last longer and recur more frequently.

Varicella zoster, a virus related to HSV, visits itching on small children via chicken pox, which also goes away in days. But the same virus causes herpes zoster that is, shingles in grown-ups. Despite its flippant handle, shingles is no laughing matter. It spreads over half the human trunk, covering either the left or right side of the backbone with band-like areas of itchy, painful blisters, and also imports that pain into the body’s interior. Zoster, too, fades away in weeks, but may recur often. That vertical delimitation of shingle’s reach betrays the neuronal origin of herpes simplex and zoster viruses.

Pathogenic Track From Lip To Brain

Finally, at its most life threatening, herpes simplex may attack the brain itself with encephalitis. “Start giving acyclovir promptly,” the medical textbook says, “before the patient lapses into a coma” with a likely mortality rate of 70 percent.

Acyclovir (made by GlaxoSmithKline plc) was originally reported in the medical literature in 1977, to relieve the agonies of genital herpes. It was not approved and licensed for sale in the U.S. until 1982, after safety and efficacy clinical trials. Acyclovir has since become the unique and all-purpose antiviral medication.

A “News & Views” commentary in the April Nature Medicine notes, “The viral specificity of acyclovir results, in part, from the fact that HSV thymidine kinase initiates the activation of the drug.” After citing acyclovir’s clinical pluses and minuses, the editorial observes that “new therapies are clearly needed.”

They are, in fact, on the way. Bayer AG Pharma Research, of Wuppertal, Germany, and Boehringer Ingelheim Pharmaceuticals Inc., of Ridgefield, Conn., both have preclinical antiviral compounds on their front burners. Back-to-back, look-alike articles describe them in Nature Medicine: Ingelheim’s paper is titled: “Herpes simplex virus helicase-primase inhibitors are active in animal models of human disease.” Bayer’s paper bears the title: “New helicase-primase inhibitors as drug candidates for the treatment of herpes simplex disease.” Wrapping up both presentations is that News & Views item, headed: “New anti-HSV therapeutics target the helicase-primase complex.”

This complex consists of three viral proteins, encoded by three genes. They act jointly to unwind double-stranded viral DNA, and generate primers for DNA synthesis by the viral DNA polymerase. Both drugs act orally.

Bayer’s compound, its paper reported, speeded up the healing of herpes lesions in a mouse model of the infection, and reduced the severity and frequency of occurrence in the disease. Similarly, Ingelheim’s preclinical drug proved highly effective against skin and vaginal herpes in mice.

“The evidence that drug resistance to helicase-primase inhibitors occurs with less frequency than resistance to acyclovir,” the N&V observed, “is promising, but must be confirmed in the clinic.” The commentary concluded: “Despite the potential promise of these new drugs, however, neither they nor the nucleoside analogs specifically, acyclovir can eliminate virus in the latent state.”

Latency is HSV’s ultimate ace in the hole literally. Between assaults on its victim’s lips, genitals, eyes, brain and body generally, herpes simplex virus holes up deep in the nervous system. First, infection of sensory nerves causes local, initial viral replication. Then the virus hitches rides on neuronal axons until it hunkers low down in dorsal root ganglia notably the trigeminal ganglion. Ganglia are clusters of neuronal cells and nerve axons. This large, flattened ganglion lies near the temporal bone at the temple of the skull near the ear. It’s the nerve area that governs the side of the mouth and the skin. The main factor in latency is HSV’s ability to curb its gene expression.

Wake-Up Heads-Up Can Be Painful

When the virus is in the ganglion, it’s producing no damage, and clearly people are not aware that there’s anything going on. But when the virus reactivates from the neuron, its awakening is frequently associated with severe prodromal pain. The hurt is perceptible before there’s anything to see on the skin, but then after two or three days epidermal blisters and lesions can appear.

Just as puzzling as the latency signal is what triggers the wake-up call that reactivates the hibernating virus. It travels back down the sensory nerves and flips the cold-sore and genital-lesion switches on again. This recurrence of painful symptoms can last for the patient’s life. Immunosuppression later in life as in HIV can reignite the latency to flare up, enlisting the immune system in very severe, systemic and often fatal infection.

Virologist Clyde Crumpacker is co-author of the News & Views commentary, and an infectious disease specialist at Harvard-affiliated Beth Israel-Deaconess Medical Center in Boston. “In such intimate association with human genes,” he told BioWorld Today, “herpes simplex viruses, in latency, persist for the life of their human host. And only their periodic reactivation causes disease. It’s estimated that 90 percent of us in the Boston area harbor antibodies against HSV-1,” he went on, “but maybe only half of the population ever has a cold sore throughout their whole life. So it’s a real mystery why this infection is controlled in some but not in others. If we can ever understand this,” he concluded, “we’d have a really important handle on how viruses and other microbes can interact with a human host.”