Step Perspective, Volume 5, Number 1; A Publication Of The Seattle Treatment Education Project - February 1993
Tim Schacker, MD

EBV has been linked to lymphoma (a cancer of the lymph glands) and is the cause of oral hairy leukoplakia, a common HIV related condition that results in discoloration of the sides of the tongue. CMV can cause an infection of the retina that leads to blindness if left untreated, it also causes erosions in the esophagus (throat) and colon. VZV causes chicken pox in younger people and shingles in older people. In HIV infection shingles can be prolonged and very painful. HHV6 has only recently been discovered. It causes an illness in young children that is characterized by very high fevers, however its role in adult illness (or in the immunocompromised person) has yet to be determined. Finally, HSV1 and HSV2 are the herpes viruses most people are familiar with. Both viruses cause painful, recurrent attacks of blister formations on the skin and mucous membranes. HSV1 is typically thought of as causing disease in the mouth and on the lips. HSV2 has traditionally been associated with genital infections. However, either virus can cause problems on the skin and mucous membranes almost anywhere on the body. HIV infected people who have been infected with HSV1 or HSV2 (or both) in the past, often have frequent and sometimes prolonged outbreaks of herpes on their genitals, rectum, or mouth.

The reason members of the herpes family of viruses can cause recurrent problems in the same person is because they have a property called latency. Most viruses (like the flu virus) will infect a person and cause a brief illness. After the person gets better, they will not have a problem with that same virus again. Herpes viruses, on the other hand, infect the individual causing initial symptoms like the painful blistering episodes of HSV2 or chicken pox from VZV, and then establish themselves in some space in the body, usually in a particular cell type. The virus is able to maintain itself in that space for the life of the Emerson, occasionally reactivating and causing symptoms, such as when VZV reactivates and causes shingles. Most scientists believe that a healthy immune system keeps the latent herpes virus under control, preventing reactivation except during periods of unusual stress or illness. When the immune system is damaged by HIV infection the virus can reactivate more easily and possibly with increased frequency. These are the reasons people with HIV infection become ill with CMV retinitis, EBV related lymphoma, and recurrent HSV.

The relationship between HIV and the herpes viruses may be more complicated than simply frequent reactivation because of advancing immunosuppression. Several investigators have experimented with these viruses in the laboratory, using molecular technology to test for possible interactions. It is possible to take part of the DNA (the chemical code that is the most basic structure, the so called "building blocks of life") from a herpes virus and join it to part of DNA from HIV. When that happens, in some cases, it is possible to change the rate at which the HIV portion of the DNA in the test tube can duplicate. In some cases duplication is faster, and in some cases slower. Based on this set of laboratory experiments, some scientists believe that HIV may act differently in people infected with one or more of the herpes viruses. However, there is almost no clinical data to look at for evidence of this interaction in humans, and often what happens in the test tube is a poor predictor of what happens in life.

What is known is that most people infected with HIV have been exposed to most of the herpes viruses. Over 95% of gay men in the United States have been exposed to HSV1 or HSV2 in the past. Sometimes the infection occurs and the person doesn't know it ever happened. Similarly, most gay men have been infected with CMV, sometimes with multiple strains of CMV. Almost the entire adult population has been infected with HHV6 and VZV, and many have been infected with EBV. The impression of many physicians who care for large numbers of HIV infected people is that patients have more severe and frequent problems with reactivations of herpes viruses. While this certainly may be true, the frequency, duration, and severity of reactivation infections has never been studied in a systematic way.

One year ago, the University of Washington began a large study to investigate the natural history of herpes viruses in HIV infected people. Study participants were asked to perform daily home cultures for HSV of the mouth, rectum, and genitals for a period of two months. This was to determine the rate of reactivation of both symptomatic and asymptomatic HSV and the sites the virus was reactivating at. Immunocompetent people who have been infected with HSV are expected to reactivate HSV between one and two percent of the time. Often these reactivations are without symptoms, i.e. the person is shedding live virus but has no symptoms (asymptomatic shedding). In addition, the volunteers were asked to return once a month for nine months. Each month blood, saliva, and urine were obtained to look for evidence of the other herpes viruses and to do specialized HIV cultures and blood tests.

Thus far, there are 22 people in the study, one-third the number ultimately needed. These volunteers have contributed an enormous amount of information about the natural history of herpes and HIV infection. Some of that information was presented at the Interscience conference on Antimicrobial Agents and Chemotherapy (ICAAC) conference held in Los Angeles last October. These 22 people all had evidence of past infection with HSV1, HSV2, or both. Many of them knew they had been infected with HSV in the past, but some did not. After analysis of more than 3,000 HSV cultures it was discovered that this group of individuals is shedding HSV at a surprisingly high rate. Often without symptoms. The rate of shedding may be correlated to HSV type, those with past evidence of HSV2 infection shed HSV2 up to 12 percent of the time (compared to one to two percent of immunocompetent people) and those with past evidence of HSV1 infection shed less than two percent of days. In people infected with both HSV1 & HSV2, 11 percent of shedding days are asymptomatic and one percent are symptomatic. These data must be interpreted with extreme caution at this point. Not enough people have been studied to draw specific conclusions, the entire projected group of 60 will have to be studied for that. There certainly is not enough information to predict the significance of these findings, except to say that HIV infected people are at greater risk for unknowingly transmitting HSV to sexual partners. Many people have asked, after reviewing this data, if the antiviral drug acyclovir should be routinely prescribed for people with past HSV2 or HSV 1&2 infection to stop this shedding. There is not enough information to justify that. Most shedding is without symptom, and therefore the individual doesn't know he or she has it. The only risk is to sexual partners, who will be protected if safe sex is practiced. Hopefully when the study has been completed the researchers will be able to answer some of these questions.

The information collected on CMV, EBV, or HHV6 has not yet been analyzed. That process is ongoing, however volunteers are still being recruited for the study. Even people with no knowledge of prior HSV1 or HSV2 infection are encouraged to call, because there is al likelihood that the individual was unknowingly infected sometimes in the past. People who qualify and agree to participate in the protocol will receive frequent blood monitoring of CD4 count and other measurements of immune function as well as first hand information about the activity of herpes viruses. In addition, all blood test results will be made available to the individual and to their health care provider (if requested). Participants will receive up to $300 for completing the protocol. For further information about this project, call Tim Schacker, M.D. or Ardeth Dunne, P.A.C. at the University of Washington ACTU (223-3184).
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