Among HIV-infected people, Kaposi sarcoma continues to be the most common malignancy diagnosed in sub-Saharan Africa and among men who have sex with men (MSM). This is a direct result of two factors the high prevalence of Kaposi sarcoma-associated herpesvirus (KSHV, also known as human herpesvirus 8) and the powerful effect of HIV-related immune perturbation to transform asymptomatic KSHV infection to malignant Kaposi sarcoma. Even though the risk is reduced by approximately 90% when HIV replication is controlled with combination antiretroviral therapy (cART) , AIDS Kaposi sarcoma cases continue to appear. The paper by Sullivan et al. in this issue of AIDS helps to clarify the impact of cART on the regulation of KSHV and, ultimately, on the risk of AIDS Kaposi sarcoma. They report that 272 MSM who received cART for 24 months, including 22 who had Kaposi sarcoma at baseline, experienced a substantial decline in the prevalence of KSHV viremia and substantial increases in the prevalence and levels of anti-KSHV antibodies.
Because KSHV is the primary cause of Kaposi sarcoma , understanding its lifecycle, pathogenic mechanisms and immunological control is central to preventing Kaposi sarcoma. Like all herpes viruses, the KSHV lifecycle has two distinct phases, both of which probably contribute to the development of Kaposi sarcoma. In the lytic phase, the majority of KSHV's 84 genes are expressed in a tightly regulated cascade to produce virions that disseminate the infection to susceptible people and to susceptible cells in vivo. Lytic expression may be required to infect endothelial cells that are precursors of the malignant Kaposi sarcoma spindle cells [5,6]. In the latent phase, KSHV is maintained as a nuclear episome that requires only a few genes for replication and distribution to daughter cells during mitosis . Spindle cells of Kaposi sarcoma lesions consistently and strongly express the latency-associated nuclear antigen (LANA). In addition, the expression of lytic genes in a few cells in each lesion may propagate both the infection and the malignancy.
How the host controls KSHV and the dysfunction that results in Kaposi sarcoma remain undefined. Detection of KSHV genome in peripheral blood mononuclear cells is highly predictive of the subsequent development of AIDS Kaposi sarcoma [8,9] and is also associated with advanced stage and likelihood of progression of AIDS Kaposi sarcoma and non-AIDS Kaposi sarcoma [10–12]. Thus, correlates of KSHV viremia provide some insight. Pellet et al. noted that cART-related clearance of KSHV viremia predicted a faster time to response of AIDS Kaposi sarcoma, with a median time to response of 251 days. In the report by Gill et al., AIDS Kaposi sarcoma responses to cART were a bit faster, but also closely tied to clearance of KSHV viremia. Without considering Kaposi sarcoma, Bourboulia et al. noted that KSHV viremia (both cell-associated and in plasma) fell substantially, often to undetectable, with cART, but only after 12–24 months. In the current study, at cART initiation KSHV genome was detected in serum in seven (35%) of 22 Kaposi sarcoma cases and also in 10 (4%) of 250 other MSM. After 24 months on cART, serum viremia had cleared in all of these except one Kaposi sarcoma case. Of note, however, seven MSM who were negative for serum viremia at baseline, were positive after 24 months on cART .
Long-term use of effective cART may affect KSHV, and directly or indirectly Kaposi sarcoma, through humoral immunity. Kaposi sarcoma is associated with higher levels of anti-KSHV antibodies [9,11,15]. In part, this merely reflects the high burden of KSHV antigens among patients who have established Kaposi sarcoma. In addition, antibody titers probably increase over time owing to ongoing, low level expression of KSHV antigens [16,17]. Without Kaposi sarcoma, antibody levels against conventional latent (LANA) and lytic (predominantly K8.1) antigens tend to be correlated, but there also are substantial differences in levels among individuals. Importantly, the possibility that serologic responses could reduce Kaposi sarcoma risk was suggested by one study that observed significantly reduced levels of KSHV neutralizing antibody levels among MSM with AIDS Kaposi sarcoma  and another that observed an inverse association between anti-KSHV titer and likelihood to develop a new Kaposi sarcoma lesion within 3 months . Sullivan et al. now report increases in seroprevalence and levels of both anti-LANA and antilytic antibodies over the course of 24 months of cART. These results partially conflict with a much smaller study that observed cART-related increases in antilytic (K8.1) but not anti-LANA antibodies . In either case, the data are insufficient to determine whether the seroconversions during cART are owing to incident KSHV infection or to recovery of humoral response against an earlier, ‘occult’ KSHV infection.
With established Kaposi sarcoma or with untreated HIV infection, T-cell responses against KSHV are seldom detected [14,19–21]. In contrast, one-quarter of HIV-negative MSM may demonstrate T-cell proliferation against disrupted whole KSHV virions . Of interest, the prevalence and strength of responses to KSHV peptides increase with cART-induced immune reconstitution [14,19,22–24]. Despite these encouraging reports, the effects of cART-generated T-cell responses on KSHV viremia and Kaposi sarcoma lesions have been inconsistent and required many months to discern.
Understanding the immunological control of KSHV and the process that results in Kaposi sarcoma continues to be hampered by the limited tools that are available. Assays to detect and quantify serum antibodies against a wider array of KSHV antigens may prove helpful [25,26]. In the meantime, we are left with impressions based on limited data. Use of cART clearly reduces the onset of Kaposi sarcoma and, over a period of many months to years, improves or clears Kaposi sarcoma lesions in the majority of patients. Over the same months to years, cART also has positive, but poorly defined, effects against KSHV. This latter impression is primarily based on studies of KSHV viremia, but companion studies of the effect of cART on KSHV shedding in saliva are needed [11,27].
As we reduce Kaposi sarcoma-related morbidity and mortality by administration of cART, we must be cognizant that long-term control of AIDS Kaposi sarcoma, as well as control of non-AIDS Kaposi sarcoma, will depend on drugs, or ideally vaccines, targeted to critical steps in the life cycle of KSHV. This virus has many ways to evade, suppress, and even subvert immune responses [6,28–31], presenting major challenges that we must accept.
1. Clifford G, Polesel J, Rickenbach M, Maso L, Keiser O, Kofler A, et al
. Cancer risk in the Swiss HIV Cohort Study: associations with immunodeficiency, smoking, and highly active antiretroviral therapy. J Natl Cancer Inst 2005; 97:425–432.
2. Sullivan S, Hirsch HH, Franceschi S, Steffen I, Boffiel-Amari E, Mueller NJ, et al.Kaposi sarcoma herpes virus antibody response and viraemia following highly active antiretroviral therapy in the Swiss HIV Cohort Study.AIDS
3. Moore PS, Chang Y. Kaposi's sarcoma (KS), KS-associated herpesvirus, and the criteria for causality in the age of molecular biology. Am J Epidemiol 1998; 147:217–221.
4. Miller G, Heston L, Grogan E, Gradoville L, Rigsby M, Sun R, et al
. Selective switch between latency and lytic replication of Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus in dually infected body cavity lymphoma cells. J Virol 1997; 71:314–324.
5. Ganem D. KSHV and the pathogenesis of Kaposi sarcoma: listening to human biology and medicine. J Clin Invest 2010; 120:939–949.
6. Schulz T. The pleiotropic effects of Kaposi's sarcoma herpesvirus. J Pathol 2006; 208:187–198.
7. Chen L, Lagunoff M. Establishment and maintenance of Kaposi's sarcoma-associated herpesvirus latency in B cells. J Virol 2005; 79:14383–14391.
8. Whitby D, Howard MR, Tenant-Flowers M, Brink NS, Copas A, Boshoff C, et al
. Detection of Kaposi sarcoma associated herpesvirus in peripheral blood of HIV-infected individuals and progression to Kaposi's sarcoma. Lancet 1995; 346:799–802.
9. Engels E, Whitby D, Goebel PB, Stossel A, Waters D, Pintus A, et al
. Detection and quantification of Kaposi's sarcoma-associated herpesvirus to predict AIDS-associated Kaposi's sarcoma. AIDS 2003; 17:1847–1851.
10. Campbell TB, Borok M, Gwanzura L, MaWhinney S, White IE, Ndemera B, et al
. Relationship of human herpesvirus 8 peripheral blood virus load and Kaposi's sarcoma clinical stage. AIDS 2000; 14:2109–2116.
11. Cannon M, Dollard S, Black J, Edlin B, Hannah C, Hogan S, et al
. Risk factors for Kaposi's sarcoma in men seropositive for both human herpesvirus 8 and human immunodeficiency virus. AIDS 2003; 17:215–222.
12. Pellet C, Chevret S, Blum L, Gauvill C, Hurault M, Blanchard G, et al
. Virologic and immunologic parameters that predict clinical response of AIDS-associated Kaposi's sarcoma to highly active antiretroviral therapy. J Invest Dermatol 2001; 117:858–863.
13. Gill J, Bourboulia D, Wilkinson J, Hayes P, Cope A, Marcelin AG, et al
. Prospective study of the effects of antiretroviral therapy on Kaposi sarcoma–associated herpesvirus infection in patients with and without Kaposi sarcoma. J Acquir Immune Defic Syndr 2002; 31:384–390.
14. Bourboulia D, Aldam D, Lagos D, Allen E, Williams I, Cornforth D, et al
. Short- and long-term effects of highly active antiretroviral therapy on Kaposi sarcoma-associated herpesvirus immune responses and viraemia. AIDS 2004; 18:485–493.
15. Brown E, Whitby D, Vitale F, Marshall V, Mbisa G, Gamache C, et al
. Virologic, hematologic, and immunologic risk factors for classic Kaposi sarcoma. Cancer 2006; 107:2282–2290.
16. Biggar R, Engels E, Whitby D, Kedes D, Goedert J. Antibody reactivity to latent and lytic antigens to human herpesvirus-8 in longitudinally followed homosexual men. J Infect Dis 2003; 187:12–18.
17. Lane AS, Dollard S, Jaffe H, Offermann M, Spira T, Gunthel C, et al
. Repeated measures study of human herpesvirus 8 (HHV-8) DNA and antibodies in men seropositive for both HHV-8 and HIV. AIDS 2004; 18:1819–1826.
18. Kimball L, Casper C, Koelle D, Morrow R, Corey L, Vieira J. Reduced levels of neutralizing antibodies to Kaposi sarcoma-associated herpesvirus in persons with a history of Kaposi sarcoma. J Infect Dis 2004; 189:2016–2022.
19. Guihot A, Dupin N, Marcelin AG, Gorin I, Bedin AS, Bossi P, et al
. Low T cell responses to human herpesvirus 8 in patients with AIDS-related and classic Kaposi sarcoma. J Infect Dis 2006; 194:1078–1088.
20. Barozzi P, Bonini C, Potenza L, Masetti M, Cappelli G, Gruarin P, et al
. Changes in the immune responses against human herpesvirus-8 in the disease course of posttransplant Kaposi sarcoma. Transplantation 2008; 86:738–744.
21. Strickler HD, Goedert JJ, Bethke FR, Trubey CM, O'Brien TR, Palefsky J, et al
. Human herpesvirus 8 cellular immune responses in homosexual men. J Infect Dis 1999; 180:1682–1685.
22. Wilkinson J, Cope A, Gill J, Bourboulia D, Hayes P, Imami N, et al
. Identification of Kaposi's sarcoma-associated herpesvirus (KSHV)-specific cytotoxic T-lymphocyte epitopes and evaluation of reconstitution of KSHV-specific responses in human immunodeficiency virus type 1-infected patients receiving highly active antiretroviral therapy. J Virol 2002; 76:2634–2640.
23. Bihl F, Mosam A, Henry L, Chisholm J, Dollard S, Gumbi P, et al
. Kaposi's sarcoma-associated herpesvirus-specific immune reconstitution and antiviral effect of combined HAART/chemotherapy in HIV clade C-infected individuals with Kaposi's sarcoma. AIDS 2007; 21:1245–1252.
24. Bihl F, Berger C, Chisholm J, Henry L, Bertisch B, Trojan A, et al
. Cellular immune responses and disease control in acute AIDS-associated Kaposi's sarcoma. AIDS 2009; 23:1918–1922.
25. Burbelo P, Leahy H, Groot S, Bishop L, Miley W, Iadarola M, et al
. Four-antigen mixture containing v-cyclin for serological screening of human herpesvirus 8 infection. Clin Vaccine Immunol 2009; 16:621–627.
26. Burbelo P, Issa AT, Ching KH, Wyvill KM, Little RF, Iadarola MJ, et al.Distinct profiles of antibodies to Kaposi sarcoma-associated herpesvirus antigens in patients with Kaposi sarcoma, multicentric castleman disease, and primary effusion lymphoma.J Infect Dis
2010 [Epub ahead of print].
27. Laney AS, Cannon M, Jaffe H, Offermann M, Ou CY, Radford K, et al
. Human herpesvirus 8 presence and viral load are associated with the progression of AIDS-associated Kaposi's sarcoma. AIDS 2007; 21:1541–1545.
28. Areste C, Blackbourn D. Modulation of the immune system by Kaposi's sarcoma-associated herpesvirus. Trends Microbiol 2009; 17:119–129.
29. West J, Damania B. Kaposi's sarcoma-associated herpesvirus and innate immunity. Future Virol 2010; 5:185–196.
30. Liang C, Lee JS, Jung J. Immune evasion in Kaposi's sarcoma-associated herpes virus associated oncogenesis. Semin Cancer Biol 2008; 18:423–436.
31. Moore PS, Chang Y. Kaposi's sarcoma-associated herpesvirus immunoevasion and tumorigenesis: two sides of the same coin? Ann Rev Microbiol 2003; 57:609–639.