AIDS-related virus spreads through kissing - Herpes
DANIEL Q. HANEY / AP 9nov00

BOSTON -- A form of the herpes virus that causes an AIDS-related skin cancer appears to spread through kissing.

Herpes virus 8 was discovered six years ago and causes a skin cancer called Kaposi's sarcoma. In the United States, the cancer occurs almost exclusively in people with AIDS.

Some had suspected that the virus was transmitted through sexual intercourse, but the new research from the University of Washington, reported in Thursday's New England Journal of Medicine, contradicts that idea.

Dr. John Pauk and others tested 39 gay men who were infected with the virus but did not have Kaposi's sarcoma. They found the virus in 30 percent of their saliva samples and mouth swabs, compared with 1 percent of anal and genital samples. When present, the virus levels were also much higher in saliva than in semen.

``The important thing is it suggests that oral-oral contact plays some role in transmission, although more study is needed to confirm that,'' said Pauk.

The study also found that homosexual men who engaged in ``deep kissing'' -- kissing that involves a lot of contact with saliva -- appeared to be at substantially higher risk of catching the virus.

Kaposi's sarcoma causes purple skin blotches and can also attack the internal organs. Like many other diseases that kill people with AIDS, it usually affects those with weakened immune systems. The virus alone rarely causes sickness among people with normal disease defenses.

The research ``definitely has public health implications for people infected with HIV,'' said Dr. Ronald O. Valdiserri of the U.S. Centers for Disease Control and Prevention. However, he said there was not enough data to recommend that people with HIV avoid deep kissing.

Thirty percent to 50 percent of HIV-infected people who catch herpes virus 8 will eventually get Kaposi's sarcoma. Kaposi's sarcoma has been present for centuries in Southern Europe, the Middle East and Africa. But it was rare in the United States until the start of the AIDS epidemic in the early 1980s.

Experts say the virus is still largely confined to homosexuals in the United States, and that is why kissing has not yet spread herpes virus 8 among heterosexuals.

Dr. Anna Wald, another University of Washington researcher, noted that herpes virus 8 is closely related to the common Epstein Barr virus, which causes mononucleosis, long known as the kissing disease.

``Teen-agers tend to get this when they start kissing,'' she said. ``The reason they get Epstein Bar virus and not herpes virus 8 is that most people have Epstein Bar virus, but relatively few have herpes virus 8.''

Dr. Patrick S. Moore of Columbia University, who discovered the virus, said exposure to saliva may explain the high rate of infection in parts of Africa, where more than 70 percent of people may carry herpes virus 8.

Other forms of the herpes virus cause chicken pox, shingles, cold sores and genital herpes.

• The New England Journal of Medicine: http://www.nejm.org/content/index.asp

The Emergence of Kaposi's Sarcoma-Associated Herpesvirus (Human Herpesvirus 8)

Editorial / New England Journal of Medicine 9nov00 v.343, n.19

The concept of emerging "new" pathogens is somewhat misnamed, since these pathogens are usually old infections that have newly adapted to social and technological changes. Such is the case for Kaposi's sarcoma-associated herpesvirus, also referred to as human herpesvirus 8 (HHV-8), which was first described in 1994 and is the subject of two articles, one by Luppi et al. (1) and one by Pauk et al., (2) in this issue of the Journal.

HHV-8 is closely related to the Epstein-Barr virus (human herpesvirus 4) and infects CD19+ B cells as well as the endothelial-derived spindle cells of Kaposi's sarcoma lesions. (3) In addition to its role in Kaposi's sarcoma, the virus is known to cause a B-cell lymphoma (primary-effusion lymphoma) and a lymphoproliferative disorder of B cells (a specific subtype of Castleman's disease). Like other opportunistic infections, HHV-8 infection alone generally does not cause disease in healthy hosts. Coincident immunosuppression as a result of advancing age, AIDS, or organ transplantation is usually required before disease is manifested, and each of these conditions has become increasingly prevalent over the past several decades. Kaposi's sarcoma is traditionally separated into different types: classic, which primarily affects elderly men of Mediterranean and eastern European origin; endemic, which is common in parts of Africa; epidemic, or AIDS-associated; and transplantation-associated. All forms are characterized by HHV-8 infection and probably represent the same pathogenic process.

Unlike most herpesviruses, HHV-8 is not ubiquitous. Infection is uncommon in most of Asia, North America, and northern Europe. The rates of infection are intermediate in Mediterranean and eastern European countries and high in central and southern Africa (Table 1). This pattern of infection matches the geographic distribution of Kaposi's sarcoma in these regions before the era of AIDS. The rates of AIDS-associated Kaposi's sarcoma, of course, are highly dependent on local rates of infection with the human immunodeficiency virus (HIV). Some areas, such as Sicily and the Po Valley in Italy, have long had elevated rates of Kaposi's sarcoma in the absence of HIV infection, and these regions have recently been shown to be hot spots for HHV-8 infection. (2) The combined effects of widespread HIV and HHV-8 infection have made Kaposi's sarcoma the most common tumor in several sub-Saharan countries, where it is an important but underappreciated public health problem.

These few facts explain the modern medical mystery of the evolution of AIDS-associated Kaposi's sarcoma. Although most Americans remain at low risk for this infection, homosexual and bisexual men are at strikingly high risk as a result of sexual transmission in some form -- the subject of the report by Pauk et al. (2) It appears that the explosive occurrence of AIDS-associated Kaposi's sarcoma in the early 1980s resulted from colliding epidemics of HIV and HHV-8 infections in the homosexual and bisexual community. For a number of years, Kaposi's sarcoma in patients with AIDS was thought to be due to the HIV infection itself or to cytokines induced by the virus. However, careful epidemiologic studies by Beral et al. (5) refuted these ideas and led to the search that resulted in the discovery of HHV-8. The emergence of HHV-8 as a pathogen during the AIDS epidemic results from the fact that it shares with HIV some of the same risk factors for transmission.

Little is known about the precise way in which HHV-8 is transmitted. That it can be sexually transmitted among homosexual men has been known since the earliest serologic studies and was demonstrated directly by Martin and coworkers in population-based cohorts in San Francisco. (6) Which behavior puts homosexual men at increased risk? Receptive anal intercourse would be a reasonable culprit; however, Pauk et al., through their careful longitudinal studies of viral shedding, show that this is not likely to be the cause. Surprisingly, like its cousin Epstein-Barr virus, HHV-8 is not shed in appreciable amounts in seminal fluid or the rectum but is persistently found in the oral cavities of some patients.

For every question answered, others arise. If the virus is spread through contact with oral secretions, why isn't the infection more common among heterosexuals? Pauk et al. found that, among men who had sex with men, deep kissing with an HIV-positive partner was a risk factor for HHV-8 infection, and seroconversion studies in an Amsterdam cohort implicated oral-penile contact as the chief risk factor. (7) Because both these sexual practices are common among heterosexual couples, neither can be used to explain why male homosexual couples are at so much higher risk for HHV-8 infection.

The acquisition of the virus through exposure to saliva may account for the high rates of infection in parts of Africa, where rates exceed 70 percent. Sexual transmission of HHV-8 in Africa appears to be a relatively unimportant route, since most infections occur through some form of casual contact, particularly among young children and young adults. This pattern is similar to the pattern for hepatitis B virus, for which poverty and poor hygienic conditions increase the risk of infection. Perhaps these social conditions affect nutritional or host factors that dramatically increase susceptibility to or the transmissibility of infection. Sophisticated and rigorous analyses of this problem are urgently needed, since poverty and crowded or poor living conditions facilitate transmission of infections, from HIV to measles virus to meningococcus. Poor hygiene itself is a poorly defined epidemiologic term and is insufficient to explain the heightened transmissibility of many infectious agents through various routes in developing countries.

An emerging pathogen can take advantage not only of changes in society but also of technological innovations, such as organ transplantation. HHV-8 has been implicated in a number of additional diseases, from multiple myeloma to sarcoidosis, but these associations have not withstood sustained scrutiny. Luppi et al., (1) however, convincingly show that a newly recognized syndrome of bone marrow failure with plasmacytosis can result from primary infection with HHV-8 as a result of kidney transplantation or the receipt of autologous peripheral-blood stem cells. Autoimmune hemolytic anemia, presumably caused by the proliferation of B cells in response to the virally encoded cytokine interleukin-6, is also frequent in the form of Castleman's disease that is associated with HHV-8 infection but not in other forms of the disease. (8)

The report by Luppi et al. is a reminder that the transmission of HHV-8 through transplantation can have serious clinical complications. Thorny public health issues concerning the screening of potential organ or bone marrow donors for the virus, prophylactic treatment of transplant recipients, and the proper use of HHV-8-positive allografts must be debated by the transplantation community. These issues cannot be ignored.

Because this field is new, there is more speculation than information about the origin of HHV-8. The virus may have been introduced relatively recently into the human population from a primate reservoir. More likely, it is an ancient virus of humans that evolved with its primate host during the divergence of the Old World and New World species of monkeys. Similar viruses have been found in Old World primates. (9,10) For the clinical community, this bit of evolutionary biology has important implications. It should alert us to a potential hazard of the xenotransplantation of primate tissues, since these primate viruses may be capable of infecting humans (though poorly adapted to the task) and hence potentially pathogenic. Furthermore, lower primates are naturally infected with two distinct species of viruses resembling HHV-8. To date only one of these two viral lineages has been found in higher primates, including chimpanzees, gorillas, and humans. However, if a second HHV-8-like virus evolved with the higher primates as well, there may be an additional human herpesvirus -- "HHV-9" -- that is similar to HHV-8 waiting to be discovered. (11,12)

Patrick S. Moore, M.D., M.P.H.
Columbia University
New York, NY 10032

References

1. Luppi M, Barozzi P, Schulz TF, et al. Bone marrow failure associated with human herpesvirus 8 infection after transplantation. N Engl J Med 2000;343:1378-85.
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2. Pauk J, Huang M-L, Brodie SJ, et al. Mucosal shedding of human herpesvirus 8 in men. N Engl J Med 2000;343:1369-77.
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3. Antman K, Chang Y. Kaposi's sarcoma. N Engl J Med 2000;342:1027-38.
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4. Moore PS, Chang Y. Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8). In: Knipe D, Griffin D, Lamb R, Roizman B, Straus S, eds. Field's virology. 4th ed. Philadelphia: Lippincott, Williams & Wilkins (in press).
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5. Beral V, Peterman TA, Berkelman RL, Jaffe HW. Kaposi's sarcoma among persons with AIDS: a sexually transmitted infection? Lancet 1990;335:123-8.
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6. Martin JN, Ganem DE, Osmond DH, Page-Shafer KA, Macrae D, Kedes DH. Sexual transmission and the natural history of human herpesvirus 8 infection. N Engl J Med 1998;338:948-54.
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7. Dukers NH, Renwick N, Prins M, et al. Risk factors for human herpesvirus 8 seropositivity and seroconversion in a cohort of homosexual men. Am J Epidemiol 2000;151:213-24.
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8. Parravinci C, Corbellino M, Paulli M, et al. Expression of a virus-derived cytokine, KSHV vIL-6, in HIV-seronegative Castleman's disease. Am J Pathol 1997;151:1517-22.
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9. Rose TM, Strand KB, Schultz ER, et al. Identification of two homologs of the Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) in retroperitoneal fibromatosis of different macaque species. J Virol 1997;71:4138-44.
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10. Desrosiers RC, Sasseville VG, Czajak SC, et al. A herpesvirus of rhesus monkeys related to the human Kaposi's sarcoma-associated herpesvirus. J Virol 1997;71:9764-9.
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11. Greensill J, Sheldon JA, Renwick NM, et al. Two distinct gamma-2 herpesviruses in African green monkeys: a second gamma-2 herpesvirus lineage among old world primates? J Virol 2000;74:1572-7.
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12. Schultz ER, Rankin GW Jr, Blanc MP, Raden BW, Tsai CC, Rose TM. Characterization of two divergent lineages of macaque rhadinoviruses related to Kaposi's sarcoma-associated herpesvirus. J Virol 2000;74:4919-28.