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.
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