No single person discovered “the herpes virus,” because the herpesvirus family includes nine known human pathogens identified across more than two millennia of medical observation. The story begins with ancient Greek physicians who named the creeping skin eruptions they saw, and it winds through 18th-century clinical medicine, 20th-century cell culture breakthroughs, and modern molecular biology. Each member of the human herpesvirus family has its own discoverer, its own era, and its own surprising backstory.
Ancient Roots of the Name
The word “herpes” comes from the Greek verb herpein, meaning to creep or crawl. Greek physicians including Hippocrates used it to describe spreading skin lesions that seemed to advance across the body’s surface.1Europe PMC / PMC Central. The History of Herpes from the Earliest Times to the Nineteenth Century: With Remarks on Dermatological Lesions in General The term was not specific to what we now call herpes simplex. Ancient and medieval writers applied it to a range of creeping, vesicular, and ulcerative skin conditions, lumping together diseases we would today separate into distinct diagnoses. It would take roughly two thousand years before physicians began drawing clear lines between herpes and the other conditions it resembled.
Jean Astruc and the First Clear Description of Genital Herpes
The person who arguably dragged herpes out of diagnostic confusion and into recognizable clinical territory was Jean Astruc, a French physician and royal medical advisor. In his 1736 treatise on venereal diseases, Astruc gave an unmistakable description of genital herpes, distinguishing it from syphilis and gonorrhea. He described “venereal pustules” and vesicles on the genitals that he recognized as a distinct, non-syphilitic condition.2Europe PMC. Genital Herpes Simplex in Historical Perspective This was a significant intellectual move: syphilis dominated the thinking about sexually transmitted infections in the 18th century, and the temptation was to attribute every genital lesion to it. Astruc saw that herpes was something else entirely, even though he had no concept of viruses or what caused the vesicles he described.
Over the next century, other clinicians refined the picture. By the 1800s, doctors increasingly recognized that oral “cold sores” and genital blisters shared a pattern of recurrence and clustering that set them apart from other skin diseases. But the cause remained unknown. The germ theory of disease had not yet arrived, and viruses as a category of pathogen would not be conceptualized until the late 19th century.
Proving Herpes Was Infectious
The leap from clinical description to proving that herpes was caused by a transmissible agent happened in the early 20th century. In 1919, Alfred Grueter, a German ophthalmologist, demonstrated that fluid from human herpes lesions could produce keratitis (corneal infection) in rabbits. This was the first experimental proof that a filterable agent, what we now call a virus, caused herpes. His work built on earlier observations by Wilhelm Löwenstein, who had shown human-to-human transfer of the infection in 1919 as well.
Around the same time, pathologists began identifying the cellular fingerprints of herpes infection under the microscope. Benjamin Lipschütz described distinctive intranuclear inclusion bodies in cells infected with herpes simplex, structures that would bear his name for decades. These Lipschütz inclusion bodies became a hallmark of herpesvirus infection and remained a primary diagnostic tool well into the mid-20th century.3JAMA. Cytologic Smears in Diagnosis of Herpes Simplex, Herpes Zoster, and Varicella
The Tzanck Smear and Bedside Diagnosis
In 1947, Arnault Tzanck, a French physician, introduced a simple cytodiagnostic technique that could identify herpes infections from a smear of cells scraped from the base of a blister.4Scientific Scholar (Journal of Skin and Sexually Transmitted Diseases). Demonstration of Tzanck smear and its significance in dermatology The Tzanck smear was quick, cheap, and could be done at the bedside. It revealed the ballooning, multinucleated giant cells characteristic of herpesvirus infection. While the test could not tell you which herpesvirus was responsible, it gave clinicians something they had never had before: a rapid, practical way to confirm a herpes diagnosis in minutes rather than days. The Tzanck smear is still used in some clinical settings today, though molecular tests have largely replaced it in well-equipped labs.
A Fatal Monkey Bite and the Discovery of Herpes B
One of the darker chapters in herpesvirus history began in 1932, when a young researcher identified only as patient W.B. was bitten by an apparently healthy rhesus macaque. He died of progressive encephalomyelitis fifteen days later. Two research groups then showed that injecting the patient’s nerve tissue into rabbits produced a similar fatal disease. The pathogen was identified as a herpesvirus. Strikingly, when rhesus macaques were injected with the same tissue, they showed no symptoms at all, likely because they were already naturally infected. Albert Sabin’s group named the virus herpes B, after the patient.5Biosafety and Health. Herpes B virus: History, zoonotic potential, and public health implications
Herpes B virus (now formally Macacine alphaherpesvirus 1) remains a serious occupational hazard for anyone who works with macaques. In the monkeys themselves, the virus causes mild or invisible infections, much as HSV-1 does in humans. But when it crosses the species barrier to humans, the results can be devastating. This was an early and dramatic illustration of how a herpesvirus can be benign in one host and lethal in another.
Cell Culture Opens the Floodgates
The development of reliable cell culture techniques in the 1940s and 1950s transformed virology. Suddenly researchers could grow viruses in the laboratory, study them in isolation, and distinguish closely related pathogens from one another. This technical revolution led directly to the identification of several new human herpesviruses in quick succession.
Cytomegalovirus (CMV), now classified as human herpesvirus 5, was independently isolated by three groups. Thomas Weller, Margaret Smith, and Wallace Rowe each grew CMV from human or mouse tissues in cell culture between 1956 and 1957.6PubMed. The history of cytomegalovirus and its diseases CMV had long been suspected as a cause of congenital disease, since pathologists had noticed the distinctive “owl-eye” enlarged cells (cytomegalia) in the tissues of stillborn infants. But until cell culture made isolation possible, the virus itself could not be pinned down. Today, CMV is recognized as one of the most common congenital infections worldwide and a major threat to people with weakened immune systems.
Then, in 1964, came a discovery that would link herpesviruses to cancer. Michael Anthony Epstein, Yvonne Barr, and Bert Achong identified a new herpesvirus in cultured tumor cells derived from a Burkitt lymphoma biopsy taken from an African patient.7PubMed Central. Epstein-Barr virus and Burkitt lymphoma The virus was named Epstein-Barr virus (EBV), now classified as human herpesvirus 4. EBV turned out to be extraordinarily common, infecting the vast majority of the world’s adult population, usually without causing cancer. But its association with Burkitt lymphoma, nasopharyngeal carcinoma, and certain other malignancies made it the first human virus convincingly linked to cancer and a landmark in both virology and oncology.
Two Types, Two Territories
Clinicians had long noticed that herpes simplex infections seemed to segregate by body site: cold sores on the mouth, blisters on the genitals. But whether this reflected one virus behaving differently in different locations, or two distinct viruses, was not settled until the late 1960s. In a landmark study, Andre Nahmias and colleagues tested 91 herpes simplex virus strains isolated from various body sites using a neutralization technique against two sets of antisera. The results were striking: the virus strains sorted neatly into two distinct antigenic types. All 42 strains identified as type 2 came from genital or closely related sites. The remaining 49 strains, identified as type 1, came from everywhere else, including oral lesions, skin infections, and encephalitis.8The Journal of Immunology. Association of Antigenic Type of Herpesvirus Hominis with Site of Viral Recovery
This neat geographic division between HSV-1 and HSV-2 has blurred somewhat in more recent decades. HSV-1 now accounts for a growing share of new genital herpes infections, particularly in younger adults, likely driven by changes in sexual behavior and declining rates of childhood oral HSV-1 exposure. Still, the fundamental biological distinction between the two types remains important for prognosis, since genital HSV-1 recurs far less often than genital HSV-2.
The Cervical Cancer False Lead
The discovery that EBV could drive cancer naturally prompted a search for similar links with other herpesviruses. In the 1960s and 1970s, HSV-2 became the prime suspect for cervical cancer. Epidemiological studies found that women with cervical cancer were more likely to have antibodies to HSV-2. The idea gained enough traction that serious resources were devoted to testing it. A critical review of the evidence in 1981 scrutinized whether HSV-2 satisfied the classic criteria for establishing a pathogen as the cause of a disease.9Gynecologic Oncology. Etiology of cervical neoplasia “The herpesvirus hypothesis”—Are Koch’s postulates satisfied?
The hypothesis eventually fell apart. The real culprit turned out to be human papillomavirus, a completely different virus family, as Harald zur Hausen’s group demonstrated in the 1980s. The HSV-2/cervical cancer story is a useful reminder that correlation in epidemiology, even strong correlation, does not prove causation. HSV-2 and HPV shared similar sexual transmission routes, which explained why they often showed up together statistically, but only HPV was driving the malignancies.
Acyclovir Changes Everything
For most of the 20th century, herpes infections had no specific treatment. Patients endured recurrences with little more than symptomatic relief. That changed with acyclovir, developed by Gertrude Elion and her colleagues at Burroughs Wellcome. Acyclovir works by mimicking a building block of DNA. The virus’s own enzyme activates the drug, which then jams viral DNA replication while leaving the host’s cells largely unharmed. In animal studies, systemic acyclovir treatment proved highly effective against acute herpes simplex virus type 1 infection.10PubMed Central. Effect of acycloguanosine treatment of acute and latent herpes simplex infections in mice
Acyclovir reached clinical use in the 1980s and was transformative. It could shorten outbreaks, reduce transmission risk, and, when taken daily, suppress recurrences in people with frequent episodes. Elion shared the 1988 Nobel Prize in Physiology or Medicine for her work on rational drug design, of which acyclovir was a crowning achievement. Newer drugs like valacyclovir and famciclovir followed, improving on acyclovir’s dosing convenience, but the basic mechanism Elion’s team pioneered remains the backbone of herpes treatment today.
The Family Fills Out in the 1980s and 1990s
The late 20th century brought a rapid expansion of the known human herpesvirus roster. In 1986, Dharam Ablashi, Saira Salahuddin, and Robert Gallo’s laboratory isolated human herpesvirus 6 (HHV-6) from patients with lymphoproliferative disorders. HHV-6 was later recognized as the cause of roseola (also called sixth disease), the common childhood illness marked by sudden high fever followed by a rash. Nearly all children are infected with HHV-6 by age two.
Human herpesvirus 7 (HHV-7) followed shortly after. Independent strains were isolated from patients, and analysis showed that HHV-7 was related to but significantly different from HHV-6 and CMV. Southern blot analysis revealed that HHV-7 shared homology with HHV-6 across only about a third of the genome segments tested, and DNA sequencing of a short fragment showed roughly 57% identity with HHV-6.11PubMed Central. Human herpesvirus 7 is a T-lymphotropic virus and is related to, but significantly different from, human herpesvirus 6 and human cytomegalovirus HHV-7 is nearly as widespread as HHV-6, infecting most people in childhood, and can also cause roseola-like illness.
The ninth and most recently discovered human herpesvirus is Kaposi sarcoma-associated herpesvirus (KSHV), also called HHV-8. In 1994, Yuan Chang and Patrick Moore at Columbia University identified it by using a molecular technique to compare DNA sequences in tumor tissue from AIDS-associated Kaposi sarcoma lesions with DNA from normal tissue. The sequences they found did not match any known human virus but were clearly herpesviral. KSHV turned out to be the cause of Kaposi sarcoma, a cancer that had been recognized since the 19th century but became epidemic during the AIDS crisis.
Where Herpes Hides
A defining feature of all herpesviruses is their ability to establish lifelong latent infections. For HSV-1, this means taking up residence in sensory neurons, particularly the trigeminal ganglion for oral infections and the sacral ganglia for genital infections. During latency, the virus shuts down nearly all of its gene expression. The one major exception is a cluster of RNA transcripts called the latency-associated transcripts (LATs), which are produced abundantly even while the virus is otherwise silent.12PubMed Central. The molecular basis of herpes simplex virus latency
Understanding latency has been one of the great challenges of herpesvirus research. Because the virus is tucked inside neurons with its DNA maintained as a quiet circular molecule, it is invisible to the immune system and unreachable by antiviral drugs that target viral replication. Periodic reactivation, triggered by stress, UV exposure, fever, or immune suppression, sends virus particles back down the nerve fibers to the skin surface, producing recurrent lesions or silent viral shedding. Every human herpesvirus has its own version of this latency trick, though the details differ: EBV hides in B cells, CMV in monocytes and bone marrow progenitor cells, and VZV in sensory ganglia similar to HSV.
Evolutionary Deep Time
One of the more surprising discoveries about herpesviruses is just how old they are. Molecular clock analyses suggest the herpesvirus family as a whole traces back to the Jurassic period, with the most recent common ancestor of all herpesviruses placed at roughly 177 million years ago.13Virus Evolution. Intrahost speciations and host switches played an important role in the evolution of herpesviruses That means herpesviruses were already diversifying when dinosaurs walked the Earth and have been co-evolving with their vertebrate hosts ever since.
The two human herpes simplex viruses have their own evolutionary story. HSV-1 appears to have co-diverged with the human lineage when our ancestors split from the ancestors of modern chimpanzees, roughly 6 million years ago. HSV-2 has a stranger origin. Molecular analyses favor a scenario in which an ancestor of the chimpanzee herpesvirus crossed the species barrier into an early human ancestor, a member of the genus Homo, around 1.6 million years ago.14PubMed Central. Evolutionary Origins of Human Herpes Simplex Viruses 1 and 2 In other words, HSV-2 is not simply a diverged sibling of HSV-1. It is a virus we acquired from another primate species during the Pleistocene, probably through predation, wound contact, or some other close physical interaction between early humans and ancestral chimpanzees.15Molecular Biology and Evolution. Evolutionary Origins of Human Herpes Simplex Viruses 1 and 2
Broader comparisons across the herpesvirus family show that host-switching events like this have been surprisingly common over evolutionary time. While many herpesviruses have co-speciated with their hosts (diverging whenever their hosts did), the viral family tree is peppered with instances where a virus jumped to a distantly related host species and successfully established itself there.13Virus Evolution. Intrahost speciations and host switches played an important role in the evolution of herpesviruses
Seeing the Virus at Atomic Resolution
For most of the history covered above, researchers knew herpesviruses only through their effects: blisters, inclusion bodies, stained smears, antibody reactions. The physical structure of the virus itself remained blurry until advances in cryo-electron microscopy (cryo-EM) in the 2010s made it possible to see herpesvirus particles in extraordinary detail. In 2018, two groups independently resolved the HSV capsid structure at near-atomic resolution. One team determined the HSV-2 capsid at 3.1 angstroms, revealing a shell built from about 3,000 proteins organized into hexons, pentons, and connecting structures called triplexes. The capsid is held together by roughly 1,500 disulfide bonds and an elaborate network of protein-protein contacts, with 46 different protein conformations fitting together to form the massive quasi-symmetric shell.16PubMed. Cryo-EM structure of a herpesvirus capsid at 3.1 Å
A parallel study resolved the HSV-1 capsid along with its associated tegument proteins at up to 3.5-angstrom resolution, producing atomic models of multiple capsid and tegument protein conformations.17PubMed Central. Structure of the herpes simplex virus 1 capsid with associated tegument protein complexes These structures are not merely beautiful; they are practical. Knowing exactly how the capsid is assembled opens the door to designing drugs that could block assembly or destabilize the particle, approaches that might eventually complement or replace the acyclovir-class antivirals that have been the standard of care for four decades. The structural work also underscores just how complex herpesviruses are compared to many other virus families, a complexity that likely reflects their long evolutionary history and intimate adaptation to their hosts.
Why There Is Still No Vaccine
Given how long herpesviruses have been studied, the absence of a vaccine for HSV-1 or HSV-2 is striking. Varicella-zoster virus has an effective vaccine (the chickenpox vaccine, introduced in the 1990s), and there are vaccines in use or development for some veterinary herpesviruses. But herpes simplex has defeated every vaccine attempt so far. The reasons are rooted in the biology discussed above. The virus’s ability to hide in neurons makes it invisible to the immune response that a vaccine would boost. Even people who mount strong antibody and T-cell responses to natural infection still experience reactivations, which means that mimicking natural immunity through vaccination may not be enough.
Several vaccine candidates have entered clinical trials over the decades, targeting viral glycoproteins that the immune system recognizes. Some showed promise in animal models but failed to prevent infection or reduce recurrence in humans. More recent approaches target different aspects of the virus, including proteins involved in immune evasion or novel mRNA-based platforms. The field remains active, but the honest assessment is that a broadly effective HSV vaccine is still years away and far from guaranteed. The latency mechanism that has made herpesviruses such successful parasites for hundreds of millions of years is the same feature that makes them so hard to defeat.