What Are Herpesviruses and What Conditions Do They Cause?

Herpesviruses are a family of large, double-stranded DNA viruses that share one defining trait: once they infect you, they never leave. Nine distinct herpesviruses are known to infect humans, and collectively they cause conditions ranging from cold sores and chickenpox to certain cancers and potentially autoimmune diseases. The family is among the most complex in virology, with over 130 species classified across three taxonomic families, though only the group that infects mammals and birds contains the members that matter for human health.¹ What makes them unusual is not just the breadth of disease they cause but the biological trick that enables it: lifelong latency in specific cell types, with the ability to reactivate months, years, or decades later.

The Nine Human Herpesviruses at a Glance

The human herpesviruses are numbered HHV-1 through HHV-8 (with HHV-6 split into two species, 6A and 6B), but most are better known by their common names. HHV-1 and HHV-2 are herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), responsible for oral and genital herpes. HHV-3 is varicella-zoster virus (VZV), the cause of chickenpox and shingles. HHV-4 is Epstein-Barr virus (EBV), best known for causing infectious mononucleosis. HHV-5 is cytomegalovirus (CMV), usually harmless in healthy people but dangerous during pregnancy and in those with weakened immune systems. HHV-6 (both A and B) and HHV-7 cause roseola, a common childhood rash illness. And HHV-8 is Kaposi’s sarcoma-associated herpesvirus (KSHV), linked to several cancers.

Despite the range of symptoms they produce, all nine share a common architecture. Their genetic material sits inside a protein shell called a capsid, which is wrapped in a fatty envelope studded with surface proteins the virus uses to latch onto and enter cells. Structural studies have shown that even herpesviruses as distantly related as HSV-1, CMV, and KSHV share the same capsid geometry, built from the same basic arrangement of protein building blocks, despite their capsid proteins having very little sequence similarity.² That structural conservation hints at how ancient and successful the herpesvirus design truly is.

How Herpesviruses Hide and Persist

The most important thing to understand about herpesviruses is latency. After the initial infection clears, the virus does not disappear. It tucks a copy of its DNA into the nucleus of a specific type of host cell and goes quiet. During latency, the virus produces almost no proteins, which means the immune system has very little to detect. It does, however, produce small RNA molecules, including microRNAs, that suppress the genes needed for active viral replication and manipulate the host cell’s own machinery to avoid being destroyed.³ When the cell divides, the viral genome hitches a ride into daughter cells, silently spreading within the body without ever producing new virus particles.

Reactivation can happen at any time, triggered by stress, illness, immune suppression, or sometimes for no identifiable reason. When it does, the virus switches back to active replication, producing new viral particles that can cause symptoms and spread to other people. This cycle of dormancy and reactivation is what makes herpesvirus infections lifelong and, in many cases, recurrent.

Herpesviruses also actively sabotage the immune response even during active infection. One of their most effective strategies involves interfering with how infected cells display pieces of the virus on their surface. Normally, a protein complex on every cell acts like a display window, showing fragments of whatever the cell is making so immune cells can inspect them. Herpesviruses block this process at multiple steps: they shut down production of the display molecules, prevent viral fragments from being loaded onto them, trap the finished complexes inside the cell, or drag them off the cell surface for destruction. The result is that immune cells capable of killing infected cells simply cannot see that anything is wrong.⁴

Herpes Simplex Viruses

HSV-1 and HSV-2 are the most widely recognized members of the family. HSV-1 was traditionally associated with oral herpes (cold sores) and HSV-2 with genital herpes, but that neat division is increasingly outdated. In several high-income countries, HSV-1 has become the leading cause of first episodes of genital herpes, particularly among adolescents and young adults.⁵ The shift appears to stem from fewer children acquiring HSV-1 during childhood (through casual family contact like shared utensils or kisses), which leaves them susceptible to catching it genitally through oral sex during adolescence. In Africa, Latin America, and Southeast Asia, HSV-2 still dominates genital herpes cases, so the pattern is far from uniform worldwide.

Many people with genital HSV-2 never realize they are infected. The symptoms can be mild or absent entirely, yet infected individuals still periodically shed the virus and can transmit it to sexual partners. Antiviral treatment and condom use both reduce the risk of transmission.⁶

Both HSV types establish latency in nerve clusters called ganglia. HSV-1 typically hides in the trigeminal ganglion near the jaw, while HSV-2 favors the sacral ganglia near the base of the spine. But the viruses are not strictly confined to one body region, and either type can cause disease at either site.

Herpes in the Eye

One underappreciated consequence of HSV infection is herpes simplex keratitis, an infection of the cornea. After initial infection, the virus can reactivate from the trigeminal ganglion and travel to the eye, causing recurrent episodes of inflammation and corneal damage. Triggers for reactivation include stress, illness, immune suppression, and physical trauma to the eye.⁷ The clinical picture ranges from mild surface irritation to deep stromal disease that scars the cornea and promotes abnormal blood vessel growth. Repeated bouts of stromal keratitis can cause progressive clouding of the cornea and loss of corneal nerve sensation.⁸ In severe cases, the result is significant vision impairment or blindness.

Neurological Complications

HSV is also one of the most common causes of sporadic viral encephalitis in otherwise healthy adults. HSV-1 typically causes a devastating infection of the temporal lobe, while HSV-2 more often leads to meningitis or atypical brainstem encephalitis. HSV-2 infections of the central nervous system can present in unusual ways, including subacute encephalitis, recurrent meningitis, spinal cord inflammation, and even symptoms that mimic psychiatric illness.⁹ These cases highlight why herpes simplex is always on the differential when doctors evaluate unexplained neurological symptoms, even in young, otherwise healthy patients.

Varicella-Zoster Virus

VZV causes two distinct diseases depending on when you encounter it. The first infection, usually in childhood, produces chickenpox: a widespread, itchy, blistering rash accompanied by fever. After recovery, the virus retreats into nerve cell bodies in the trigeminal and dorsal root ganglia, where it can remain dormant for decades.¹⁰

When VZV reactivates, it causes shingles: a painful, blistering rash that typically appears in a band on one side of the body, following the path of the nerve where the virus was hiding. Shingles is most common in older adults and people with weakened immune systems, but it can strike anyone who has had chickenpox. The rash itself usually heals within a few weeks, but a subset of patients develop postherpetic neuralgia, a persistent burning or stabbing pain in the area of the rash that can last months or even years after the blisters resolve.¹¹ Shingles vaccines, now widely recommended for adults over 50, substantially reduce the risk of both the rash and the chronic pain that can follow it.

Epstein-Barr Virus

EBV infects the vast majority of the world’s population, but when you catch it determines what happens. Children who acquire EBV early in life, typically through close family contact, almost never develop symptoms. In wealthier countries with higher hygiene standards, first infection has increasingly shifted to adolescence or adulthood, at which point a proportion of people develop infectious mononucleosis (mono), characterized by severe sore throat, swollen lymph nodes in the neck, fever, and sometimes debilitating fatigue that can linger for weeks or months.¹²

EBV’s long-term significance extends well beyond mono. The virus establishes latency in B cells (a type of white blood cell), and its latent gene products can drive those cells toward uncontrolled growth. EBV is causally linked to several cancers, including nasopharyngeal carcinoma (a cancer of the upper throat common in parts of East and Southeast Asia), Burkitt lymphoma, Hodgkin lymphoma, and certain stomach cancers. In nasopharyngeal carcinoma specifically, the expression of latent EBV genes is thought to push pre-cancerous cells toward full malignancy through multiple pathways.¹³

Perhaps the most striking recent finding involves EBV and multiple sclerosis. Epidemiological evidence now indicates that EBV infection is a necessary risk factor for developing MS, though how the virus contributes remains unclear.¹⁴ Broader associations have also been reported with systemic lupus erythematosus and rheumatoid arthritis, though whether EBV actually causes these conditions or merely aggravates them in predisposed individuals is still debated.¹⁵ The idea that a virus nearly everyone carries could be a prerequisite for a disease that affects a much smaller number of people underscores how much individual genetics and immune responses shape outcomes.

Cytomegalovirus

CMV is another herpesvirus that infects a large share of the global population without most people ever noticing. In healthy adults, primary CMV infection is usually silent or produces a mild illness easily mistaken for a cold. The problems arise in two specific situations: pregnancy and immune suppression.

When a pregnant person acquires CMV for the first time (or experiences reactivation), the virus can cross the placenta and infect the developing fetus. Congenital CMV is one of the leading causes of sensorineural hearing loss in newborns and can also cause neurodevelopmental complications.¹⁶ Most congenitally infected babies appear healthy at birth, but a portion go on to develop hearing loss, vision problems, or developmental delays that may not become apparent until later in childhood. Among children born with obvious symptoms of congenital CMV, the burden is heavy: in one long-term study following 76 children to a median age of 13, roughly three-quarters developed hearing loss, over 40 percent had intellectual disability, and about a quarter had vision impairment.¹⁷

In people with weakened immune systems, such as organ transplant recipients or those with advanced HIV, CMV can reactivate and cause serious organ-specific disease. CMV pneumonitis is a well-recognized complication in transplant recipients.¹⁸ CMV retinitis, an infection of the eye that can lead to blindness, is another concern in severely immunosuppressed patients; screening protocols exist for transplant recipients, though adherence in practice can be inconsistent.¹⁹

HHV-6, HHV-7, and Kaposi’s Sarcoma Herpesvirus

Three members of the herpesvirus family get less public attention but are medically significant in their own right. HHV-6B and HHV-7 are the viruses behind roseola (also called sixth disease or exanthem subitum), a very common illness of infancy marked by several days of high fever followed by a rash that appears as the fever breaks. Febrile seizures are a frequent complication, making the illness alarming for parents even though it is almost always benign.²⁰ Nearly all children acquire HHV-6 and HHV-7 by age two or three, often without ever being formally diagnosed.

HHV-8, or Kaposi’s sarcoma-associated herpesvirus (KSHV), is far rarer in most populations but carries outsized consequences. KSHV causes three human cancers: Kaposi sarcoma (a tumor of blood vessel-lining cells), primary effusion lymphoma, and a form of multicentric Castleman’s disease. All three occur predominantly in the setting of immune deficiency, particularly HIV infection.²¹ Kaposi sarcoma was one of the defining illnesses of the early AIDS epidemic and remains common in sub-Saharan Africa. The virus promotes tumor growth in part by triggering the formation of new blood vessels and chronic inflammation, creating an environment that feeds the tumor.²²

Antiviral Drugs and Why a Cure Remains Elusive

The mainstay antivirals for herpesvirus infections, acyclovir and its relatives valacyclovir and famciclovir, work by exploiting a trick of the virus’s own biology. Herpesviruses encode their own version of an enzyme called thymidine kinase, which activates the drug inside infected cells. Once activated, the drug mimics a building block of DNA and jams the viral copying machinery. Because the drug depends on a viral enzyme to become active, it has relatively little effect on uninfected cells, which is why these medications are well tolerated.

The catch is that these drugs only work on actively replicating virus. Latent virus sitting silently in a nerve cell or B cell is not copying its DNA and is therefore invisible to acyclovir. This is the fundamental reason herpesvirus infections cannot be cured: you can suppress outbreaks, shorten them, and reduce transmission, but you cannot eliminate the latent reservoir.

Drug resistance, while uncommon in healthy people, is a real problem in immunocompromised patients who take antivirals for long periods. Resistant strains typically arise through mutations or deletions in the viral thymidine kinase gene, which prevents the drug from being activated inside the cell.²³ When that happens, clinicians must turn to second-line drugs like foscarnet or cidofovir, which work through different mechanisms but carry more side effects.

For CMV, the drug landscape is somewhat different. Ganciclovir and valganciclovir are the primary agents, and newer drugs like letermovir are used to prevent CMV reactivation after transplant. No broadly effective antiviral exists for EBV, which is why EBV-related cancers are treated with chemotherapy and radiation rather than antiviral agents.

The Vaccine Landscape

Vaccines exist for only one human herpesvirus: VZV. The childhood varicella vaccine prevents chickenpox, and the recombinant zoster vaccine (Shingrix) substantially reduces the risk of shingles and postherpetic neuralgia in older adults. Both have been major public health successes.

For the remaining eight human herpesviruses, no approved vaccines are available, despite decades of effort. The challenge is partly biological. Herpesviruses have evolved sophisticated immune evasion mechanisms, and a vaccine that induces antibodies alone may not be sufficient to prevent a virus that hides inside cells and limits its protein expression during latency. The pattern of lifelong infection with intermittent reactivation and viral shedding means a vaccine would need either to prevent infection entirely or to control the virus powerfully enough to prevent reactivation and disease.³ Several candidate vaccines for HSV-2 and CMV have entered clinical trials over the years, but none has yet succeeded in late-stage testing. A CMV vaccine remains a particular priority given the burden of congenital CMV disease.

Ancient Companions

Herpesviruses have been evolving alongside their hosts for an extraordinarily long time. Evolutionary analyses suggest that HSV-1 codivergence with humans stretches back millions of years, while HSV-2 appears to have jumped into the human lineage from the ancestor of modern chimpanzees roughly 1.6 million years ago, infecting an extinct member of the genus Homo before reaching modern humans.²⁴ That deep coevolutionary history helps explain why herpesviruses are so exquisitely adapted to human biology and so difficult to eradicate.

Herpesviruses are not unique to humans, either. Virtually every mammal, bird, reptile, and fish species that has been carefully studied carries its own herpesviruses, each finely tuned to its particular host. These viruses are typically harmless in their natural hosts but can be devastating when they cross species barriers. Herpes B virus, for instance, is carried asymptomatically by macaques. In humans, however, B virus infection can cause severe and frequently fatal encephalitis.²⁵ Human cases are rare, mostly occurring among laboratory workers and others with close macaque contact, but the fatality rate is high enough that the virus is taken very seriously as a biosafety concern.²⁶

Turning Herpesviruses Against Cancer

In an ironic twist, the same properties that make herpesviruses persistent and hard to eliminate have made them useful in cancer therapy. Oncolytic herpes simplex viruses are genetically engineered versions of HSV-1 that have been stripped of the genes they need to replicate in healthy cells but can still replicate in and destroy cancer cells. When injected into a tumor, these modified viruses kill cancer cells directly and, just as importantly, provoke an immune response against the tumor.²⁷ The first oncolytic herpes therapy, talimogene laherparepvec (T-VEC), was approved for the treatment of advanced melanoma in 2015. Researchers continue to develop next-generation oncolytic herpesviruses with enhanced tumor-killing and immune-stimulating properties, including combinations with immunotherapy drugs. It is a strange kind of poetic justice: a virus that evolved to persist in the human body indefinitely is being re-engineered to target one of medicine’s most persistent enemies.