Kaposi sarcoma-associated herpesvirus (KSHV, also called human herpesvirus 8; HHV8) is a necessary, but insufficient, cause of Kaposi sarcoma (KS) . KS is endemic in parts of Africa and also occurs opportunistically among individuals with AIDS . In HIV-negative, KSHV-seropositive adults from the Mediterranean area over the age of 50 years, approximately one in 3000 men and less than half as many women develop KS per year . In contrast, one in 30 HIV-positive, KSHV-seropositive men who have sex with men (MSM) develop KS per year . This 100-fold increased risk of KS with HIV has amplified the incidence of KS in many populations of sub-Saharan Africa, where KSHV was endemic before the AIDS epidemic. In South Africa, one in three adults are KSHV seropositive  and the risk of KS is increased more than 20-fold with HIV infection . With the HIV epidemic, KS has thus become the commonest cancer in children, women and men in many sub-Saharan African countries [7,8]. Abating this KS epidemic will require concerted efforts to treat individuals with HIV/AIDS and to reduce HIV and KSHV transmission.
How KSHV is transmitted, and whether HIV influences KSHV infectivity or vulnerability, is unknown. In sub-Saharan Africa, KSHV is transmitted during childhood [9,10], perhaps via saliva, rarely via breast milk . HIV infection was unrelated to KSHV seroincidence among 485 infants in Zambia , whereas it was associated with a twofold higher seroprevalence of KSHV among 1165 children in South Africa . These limited data suggest a null or a limited synergistic HIV effect on the risk of KSHV infection.
The sexual transmission of a ‘KS agent’ was postulated by Beral and co-workers  in 1990, on the basis of the higher risk of KS among MSM compared with other HIV exposure groups, and associations of KS with more sexual partners and sexually transmitted infections (STI) [14–16]. The discovery of KSHV followed , and seroepidemiology studies have largely confirmed sexual transmission among MSM [17,18]. Molecular studies have, however, pointed to saliva as perhaps the major vehicle of transmission, as KSHV DNA is detected much more frequently and at much higher levels in saliva than in other body fluids .
Although KS was increased in women who had a bisexual partner , the evidence for heterosexual KSHV transmission and association, if any, with HIV co-infection, is weak. These issues are especially relevant for sub-Saharan Africa. Heterosexual transmission has been inferred based on the demonstration of increasing age-specific KSHV seroprevalence , but studies are now providing specific data on sexual exposures and KSHV seropositivity. Anti-KSHV antibodies were detected more frequently (twofold) among commercial sex workers (CSW) and among other women and men who had laboratory evidence of an STI, compared with low-risk adults from a general population in Lagos, Nigeria . Furthermore, anti-KSHV antibodies were detected more frequently (twofold) among HIV-seronegative CSW in Kenya who had gonorrhea compared with those who did not . Similarly, long-distance truck drivers with syphilis were more likely to have KSHV antibodies , and several other studies have shown significant associations with multiple sexual partners , HIV infection [24,25] and genital warts .
The associations reported have, however, not been consistent within and across studies. For example, anti-KSHV antibodies were associated with syphilis in women, but not in men in Nigeria . Furthermore, among CSW in Kenya, anti-KSHV antibodies were not associated with the number of sex partners, sex acts per week, condom use, trichomonas, chlamydia, vaginal candidiasis or bacterial vaginosis . Among long-distance truck drivers in Kenya, anti-KSHV antibodies were not associated with HIV infection, having sex with prostitutes, urethral discharge or genital ulcer disease . The results were null for KSHV association with HIV, syphilis, herpes simplex virus 2, and sexual partners among 15–29-year-old individuals in a rural general population in Uganda . These inconsistencies cast doubt on whether heterosexual KSHV transmission occurs.
In this issue, Malope and colleagues (pp. 000–000) discuss these issues. They investigated whether anti-KSHV antibodies were associated with sexual activity among 2103 subjects, including miners, CSW, and adult residents of Carletonville, South Africa. Sexual behaviors were measured by questionnaire and by testing for chlamydia, gonorrhea, syphilis, and herpes simplex 2. KSHV seroprevalence was 47.5%, and STI were common (HIV 39.6%, herpes simplex 2 65.7%, chlamydia 8.2%, syphilis 8.1%, and gonorrhea 6.4%). KSHV seropositivity was unrelated to HIV, STI, or sexual partners, prompting the authors to conclude that heterosexual transmission may not contribute to KSHV spread in this South African population.
The study of Malope et al. and those reviewed above highlight challenges to determining whether KSHV is transmitted sexually. A side-by-side comparison of infections related to complex behavior is risky. Differences in cultural norms, study designs, serological assays, and analytical methods could lead to differences in results. For example, KSHV seropositivity was not associated with gonorrhea or syphilis in the study by Malope et al., but both of these STI were associated with KSHV in two studies in Kenya. It is tempting to conclude that sexual transmission does occur, because more studies seem to report positive, than null, associations of KSHV with one or more measures of sexual activity. Null studies such as those of Malope et al., however, argue against the co-transmission of KSHV with HIV or other STI. This conclusion is biologically and socially plausible. Biologically, as observed above among MSM, KSHV DNA is detected more frequently in saliva (∼30%) than in cervical fluids (4%) among Africans . Socially, the extent of salivary exchange during sexual contact among Africans is unknown; our casual impression is that kissing, as practised in western populations, is rare.
So what is the public health implication of the study by Malope et al.? First, they show high KSHV and HIV co-infection prevalence, thereby calling attention to a KS epidemic looming in the shadow of the HIV/AIDS epidemic. Effective antiretroviral therapies have substantially reduced the risk of KS in western KSHV/HIV-co-infected populations , and therefore effectively treating HIV/AIDS can immediately reduce the burden of KS in sub-Saharan Africa. A substantial risk of KS persists, however, even with effective antiretroviral therapies . An additional goal must therefore be to reduce the incidence of HIV and KSHV infections. Prevention programmes could correctly stress the likelihood of KSHV transmission via saliva and encourage an improvement in hygiene and sanitation aimed at reducing KSHV transmission among children and, possibly, adults. Clearly, the challenges to such efforts are enormous, but so are the benefits.
Conflicts of interest: None.
1. Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, Moore PS. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 1994; 266:1865–1869.
2. Boshoff C, Weiss RA. Epidemiology and pathogenesis of Kaposi's sarcoma-associated herpesvirus. Philos Trans R Soc Lond B Biol Sci 2001; 356:517–534.
3. Vitale F, Briffa DV, Whitby D, Maida I, Grochowska A, Levin A, et al
. Kaposi's sarcoma herpes virus and Kaposi's sarcoma in the elderly populations of 3 Mediterranean islands. Int J Cancer 2001; 91:588–591.
4. Engels EA, Biggar RJ, Marshall VA, Walters MA, Gamache CJ, Whitby D, Goedert JJ. Detection and quantification of Kaposi's sarcoma-associated herpesvirus to predict AIDS-associated Kaposi's sarcoma. AIDS 2003; 17:1847–1851.
5. Sitas F, Carrara H, Beral V, Newton R, Reeves G, Bull D, et al
. Antibodies against human herpesvirus 8 in black South African patients with cancer. N Engl J Med 1999; 340:1863–1871.
6. Sitas F, Pacella-Norman R, Carrara H, Patel M, Ruff P, Sur R, et al
. The spectrum of HIV-1 related cancers in South Africa. Int J Cancer 2000; 88:489–492.
7. Wabinga HR, Parkin DM, Wabwire-Mangen F, Nambooze S. Trends in cancer incidence in Kyadondo County, Uganda, 1960–1997. Br J Cancer 2000; 82:1585–1592.
8. Mbulaiteye SM, Parkin DM, Rabkin CS. Epidemiology of AIDS-related malignancies an international perspective. Hematol Oncol Clin North Am 2003; 17:673–696, v.
9. Bourboulia D, Whitby D, Boshoff C, Newton R, Beral V, Carrara H, et al
. Serologic evidence for mother-to-child transmission of Kaposi sarcoma-associated herpesvirus infection. JAMA 1998; 280:31–32.
10. Mbulaiteye SM, Pfeiffer RM, Whitby D, Brubaker GR, Shao J, Biggar RJ. Human herpesvirus 8 infection within families in rural Tanzania. J Infect Dis 2003; 187:1780–1785.
11. Brayfield BP, Kankasa C, West JT, Muyanga J, Bhat G, Klaskala W, et al
. Distribution of Kaposi sarcoma-associated herpesvirus/human herpesvirus 8 in maternal saliva and breast milk in Zambia: implications for transmission. J Infect Dis 2004; 189:2260–2270.
12. Brayfield BP, Phiri S, Kankasa C, Muyanga J, Mantina H, Kwenda G, et al
. Postnatal human herpesvirus 8 and human immunodeficiency virus type 1 infection in mothers and infants from Zambia. J Infect Dis 2003; 187:559–568.
13. Malope BI, Pfeiffer RM, Mbisa G, Stein L, Ratshikhopha EM, O'Connell DL, et al
. Transmission of Kaposi sarcoma-associated herpesvirus between mothers and children in a South African population. J Acquir Immune Defic Syndr 2007; 44:351–355.
14. Beral V, Peterman TA, Berkelman RL, Jaffe HW. Kaposi's sarcoma among persons with AIDS: a sexually transmitted infection? Lancet 1990; 335:123–128.
15. Goedert JJ, Biggar RJ, Melbye M, Mann DL, Wilson S, Gail MH, et al
. Effect of T4 count and cofactors on the incidence of AIDS in homosexual men infected with human immunodeficiency virus. JAMA 1987; 257:331–334.
16. Beral V, Bull D, Darby S, Weller I, Carne C, Beecham M, Jaffe H. Risk of Kaposi's sarcoma and sexual practices associated with faecal contact in homosexual or bisexual men with AIDS. Lancet 1992; 339:632–635.
17. O'Brien TR, Kedes D, Ganem D, Macrae DR, Rosenberg PS, Molden J, Goedert JJ. Evidence for concurrent epidemics of human herpesvirus 8 and human immunodeficiency virus type 1 in US homosexual men: rates, risk factors, and relationship to Kaposi's sarcoma. J Infect Dis 1999; 180:1010–1017.
18. Martin JN. Diagnosis and epidemiology of human herpesvirus 8 infection. Semin Hematol 2003; 40:133–142.
19. Pauk J, Huang ML, Brodie SJ, Wald A, Koelle DM, Schacker T, et al
. Mucosal shedding of human herpesvirus 8 in men. N Engl J Med 2000; 343:1369–1377.
20. Olsen SJ, Chang Y, Moore PS, Biggar RJ, Melbye M. Increasing Kaposi's sarcoma-associated herpesvirus seroprevalence with age in a highly Kaposi's sarcoma endemic region, Zambia in 1985. AIDS 1998; 12:1921–1925.
21. Eltom MA, Mbulaiteye SM, Dada AJ, Whitby D, Biggar RJ. Transmission of human herpesvirus 8 by sexual activity among adults in Lagos, Nigeria. AIDS 2002; 16:2473–2478.
22. Lavreys L, Chohan B, Ashley R, Richardson BA, Corey L, Mandaliya K, et al
. Human herpesvirus 8: seroprevalence and correlates in prostitutes in Mombasa, Kenya. J Infect Dis 2003; 187:359–363.
23. Baeten JM, Chohan BH, Lavreys L, Rakwar JP, Ashley R, Richardson BA, et al
. Correlates of human herpesvirus 8 seropositivity among heterosexual men in Kenya. AIDS 2002; 16:2073–2078.
24. Hladik W, Dollard S, Downing R, et al
. Kaposi's sarcoma in Uganda: risk factors for human herpesvirus 8 infection among blood donors. J Acquir Immune Defic Syndr 2003; 33:206–210.
25. Klaskala W, Brayfield BP, Kankasa C, Bhat G, West JT, Mitchell CD, Wood C. Epidemiological characteristics of human herpesvirus-8 infection in a large population of antenatal women in Zambia. J Med Virol 2005; 75:93–100.
26. Wawer MJ, Eng SM, Serwadda D, Sewankambo NK, Kiwanuka N, Li C, Gray RH. Prevalence of Kaposi sarcoma-associated herpesvirus compared with selected sexually transmitted diseases in adolescents and young adults in rural Rakai District, Uganda. Sex Transm Dis 2001; 28:77–81.
27. Taylor MM, Chohan B, Lavreys L, Hassan W, Huang ML, Corey L, et al
. Shedding of human herpesvirus 8 in oral and genital secretions from HIV-1-seropositive and -seronegative Kenyan women. J Infect Dis 2004; 190:484–488.
28. Biggar RJ, Chaturvedi AK, Goedert JJ, Engels EA. AIDS-related cancer and severity of immunosuppression in persons with AIDS. J Natl Cancer Inst 2007; 99:962–972.
29. Engels EA, Pfeiffer RM, Goedert JJ, Virgo P, McNeel TS, Scoppa SM, Biggar RJ. Trends in cancer risk among people with AIDS in the United States 1980–2002. AIDS 2006; 20:1645–1654.