Why does herpes simplex tend to recur

Herpes simplex virus HSV is a common ocular infection. Approximately , persons in the United States have experienced ocular HSV disease and there are approximately 50, new and recurrent cases each year.

Even though an individual may not have had clinically apparent disease, high fever, immunosuppression, and sometimes surgery can reactivate latent herpes. Our work on herpes began 41 years ago in a condemned building at the Massachusetts Eye and Ear Infirmary in Boston Fig. The animal room on the second floor was easy to recognize, because it was the only air-conditioned room in the building. Emily Varnell, then a young chemical engineer, came to work with me and has worked with me ever since in trying to treat and prevent recurrences of herpes.

My initial theory was that viral disease could be treated by identifying a drug that would bind to DNA polymerase, a virus-specific enzyme responsible for the final assembly of viral DNA.

The first candidate was idoxuridine, which had been synthesized as a potential anticancer agent by William Prusoff at Yale 8 years before and was the only drug at that time known to react with DNA polymerase. To maintain this round-the-clock schedule, Emily Varnell, Anthony Nesburn, and I took turns sleeping on a cot in the animal room and waking up every 2 hours throughout the night.

These experiments demonstrated that the treatment was successful, and the results of these and subsequent experiments established that it is possible to treat virus disease, that nucleosides are effective for this treatment, and that nucleosides can achieve this effect by binding to the DNA polymerase.

Nucleoside antivirals fall into two categories. Nucleosides with abnormal bases, such as idoxuridine and trifluridine, form a DNA code that cannot be read by the viral enzymes, so that the virus cannot reproduce.

Nucleosides with abnormal sugars, such as acyclovir and famciclovir, bind to viral DNA polymerase or act as terminators of the sugar backbone of DNA, resulting in incomplete DNA chains that prevent replication of the virus.

Eventually, it became apparent that although some ocular viral disease is caused predominantly by multiplying virus, other ocular disease is largely a hypersensitivity reaction to viral antigens. To treat the hypersensitivity component, the combination of corticosteroids and antivirals was introduced, 4 and this combination is still in use today.

The next question we asked was, why do only some people get disease, and why is some disease severe and some very mild i. To shed light on the role of the genetic heterogeneity of HSV in causing different types of disease, we isolated viruses from many different patients and used the virus isolates to infect rabbits. We found that some isolates caused mild disease, some caused moderate disease, and some caused severe disease, but each isolate had its own characteristics and was different from other isolates Fig.

For example, some isolates caused long dendrites, others middle-sized dendrites, and still others small punctate lesions Fig. We also found that the genes causing stromal disease segregated separately from those causing epithelial disease.

Thus, it was shown that the character of disease is determined, at least in part, by the infecting virus. At the time of initial infection, HSV-1 travels to the neural ganglion and becomes latent, conferring a lifetime infection.

We also know that once a ganglion is infected by one strain of the virus, it is generally resistant to superinfection, even though peripheral infection by other virus strains may occur. It seems clear, however, that the initial infecting virus is most often responsible for recurrent infections throughout life. A major question regarding herpes therapy concerns the role of systemic antiviral treatment of ocular disease, especially now that topical antiviral agents permit the rapid treatment of epithelial disease.

The first was, does acyclovir effectively treat stromal disease and iritis? The disappointing answer was that it does not. Again, the answer was no. Here, the answer was yes: Symptoms disappeared and vision improved more rapidly, although the final outcomes in terms of visual acuity and recurrences after treatment was discontinued were similar, whether the patients received steroids or not.

The answers were no, no, and no, and, furthermore, no increases in recurrences were observed in patients followed for 6 months after steroids were discontinued. The good news was that acyclovir clearly reduced the recurrence rate. Even with systemic acyclovir treatment, more than half of the patients with ocular herpes had recurrences, and it is the problem of continued recurrences that leads to continued morbidity and blindness.

Similarly, we know that, in genital herpes and other herpetic diseases as well, acyclovir provides incomplete protection against recurrences, does not prevent shedding of virus in bodily fluids, and does not prevent the spread of disease. Over the years, we have examined a variety of possible approaches to the prevention of recurrent disease.

The first began with the finding of Bobek and Cheng that it is possible to synthesize an inhibitor of viral thymidine kinase: The result was ethynylthymidine. I knew, however, that the central nervous system did not normally contain thymidine kinase and that viral mutants deficient in thymidine kinase generally do not recur frequently.

We found that, in fact, ethynylthymidine reduced the recurrence rate of herpes, but it is insoluble and difficult to administer, and the reduction in recurrence rate, although significant, would not be clinically useful. Next, Gebhardt refined a mouse heat stress model 18 in which mice that had been infected with herpes and allowed to recover were immersed in warm water for a period of 10 minutes, producing reactivation of herpes Fig.

In this model, he found that acyclovir was relatively effective in inhibiting viral multiplication on the surface of the cornea, but had little effect in inhibiting viral reactivation in the trigeminal ganglion, even when given before heat stress was applied Gebhardt BM, unpublished data, We thought that epinephrine, which Kwon and Hill have shown to cause reactivation of herpes in rabbits Kwon et al.

We found that propranolol reduced reactivation of herpes in mice, but this reduction, although significant, did not appear sufficient to justify the use of drugs that had significant side effects 22 Table 1. In a controlled rabbit study, we found that latanoprost made herpes keratitis worse and increased recurrences of herpes significantly.

We also found that unoprostone Fig. There was a flurry of interest in a connection between prostaglandins and herpes approximately 20 years ago, at which time prostaglandins were shown to enhance the spread of herpes virus in cell culture 26 27 and to inhibit interferon production 27 28 and were implicated in the reactivation of herpetic skin lesions. More recently, Athar et al. All these findings suggest that the prostaglandin system may play a critical role in both the multiplication and reactivation of herpes.

It may even account for the reduction of recurrences we observed after propranolol treatment in mice, because as a treatment for glaucoma, epinephrine is known to induce the secondary formation of prostaglandins, and COX inhibitors that prevent prostaglandin synthesis also prevent the ocular hypotensive effect of epinephrine in both animals and humans.

It seems reasonable that activation of a COX-2 gene may well be a cellular mechanism important in the induction of herpetic recurrences. Clearly changes within the cell occur that stimulate the virus to reproduce.

Gebhardt and I unpublished data and later Hill et al. In mice examined within an hour after the application of heat stress alone, only COX-2 and heat shock protein genes were activated Fig. If, in fact, these heat-stressed animals that are prone to herpes recurrences require the induction of the COX-2 gene to induce the recurrences, perhaps agents that inhibit this process would also be effective in preventing the recurrences.

Gebhardt found that aspirin was effective in inhibiting recurrences of herpes Gebhardt BM, unpublished data, and that the highly specific COX-2 inhibitor 5,5-dimethyl 3-fluorophenyl 4-methylsulfonyl phenyl-2 5H -furanone DFU 35 is even more effective. In both cases, the inhibition of recurrences was accompanied not only by a reduction of virus on the corneal surface, but also by a reduction of virus DNA in the ganglion.

These and other studies from our laboratories suggest that there are significant differences in cyclooxygenase inhibitors. This research, although early and in many ways preliminary, suggests for the first time that the induction of a cellular gene may cause viral recurrence.

If so, it may be possible to prevent and treat viral disease by inhibiting a cellular gene pathway induced by specific stimuli, and the relevant drugs are available and safe. It is likely that this pathway is important and that inhibitory drugs will be effective against labial herpes, HSV-2, perhaps CMV, and varicella zoster virus.

In fact, the drugs may be therapeutic as well as preventive, in that latanoprost makes infection worse and COX-2 inhibitors reduce CMV multiplication. It is possible that COX-2 inhibition will be topically effective in the eye the latanoprost effect was topical , even though an initial trial with the nonsteroidal anti-inflammatory drug ketorolac did not show therapeutic efficacy. It is also likely that these agents will be additive to antivirals and may help prevent spread of the virus if they prevent recurrences or viral reactivation in the ganglion.

This article looks at the causes, their symptoms, and some treatment and prevention…. Many people develop pimples on their genitals. Sometimes, these pimples resemble lesions caused by the herpes simplex virus. Although genital pimples…. Genital herpes is a sexually transmitted infection. It can cause blisters and sores around the genitals and anus, but it may cause no symptoms. Anal herpes is a form of genital herpes. Like genital herpes, it is caused by HSV-2 and is passed on through sexual contact.

Anal herpes causes…. Symptoms, causes, and treatment of herpes. Pictures Symptoms Causes Treatment Prevention tips We include products we think are useful for our readers. Prevention tips. Exposure to air pollutants may amplify risk for depression in healthy individuals. Costs associated with obesity may account for 3. Related Coverage. Valacyclovir Valtrex and cost. Medically reviewed by Purva Singla, PharmD. What causes genital sores in females? Medically reviewed by Carolyn Kay, MD.

Telling the difference between genital pimples and herpes. Medically reviewed by Holly Ernst, P. What to know about genital herpes. Medically reviewed by Jill Seladi-Schulman, Ph. When inactive, the virus lies dormant in a group of nerve cells. While some people never develop any symptoms from the virus, others will have periodic outbreaks of infections.

Oral herpesis spread most commonly from individuals with an active outbreak or sore. You can catch oral herpes by engaging in intimate or personal contact e.

The initial primary infection of oral herpes is usually the worst. It may cause severe, flu-like symptoms, including swollen lymph nodes and headache. However, some people have no symptoms at all. During the initial infection, sores can occur on and around the lips and throughout the mouth. Recurring infections tend to be much milder, and the sores usually erupt on the edges of the lips.

Some people never have any additional outbreaks beyond the initial infection. The following are the most common signs and symptoms of a recurring oral herpes simplex virus infection. Painful, fluid-filled blisters may appear on the lips or under the nose. The blisters and fluid are highly contagious.