Human Herpesvirus 8 Seropositivity and Risk of Kaposi's Sarcoma and Other Acquired Immunodeficiency Syndrome-Related Diseases

Rezza, Giovanni; Andreoni, Massimo; Dorrucci, Maria; Pezzotti, Patrizio; Monini, Paolo; Zerboni, R; Salassa, Benardino; Colangeli, Vincenzo; Sarmati, Loredana; Nicastri, Emanuele; Barbanera, M; Pristerà, Raffaele; Aiuti, F; Ortona, L; Ensoli, Barbara

doi:10.1093/jnci/91.17.1468

Cited by 121 publications

(81 citation statements)

References 36 publications

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“…KS is the most common neoplasm in AIDS patients (5,6). The KSHV genome encodes multiple molecules that trigger cell proliferation and induce tumor formation, recapitulating some key pathological features of KSHV-associated malignancies.…”

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confidence: 99%

IKK epsilon kinase is crucial for viral G protein-coupled receptor tumorigenesis

Wang

Zhu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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G protein-coupled receptors (GPCRs) are seven-transmembrane proteins that transmit diverse extracellular signals across a membrane. Herpesvirus genomes encode multiple GPCRs implicated in viral pathogenesis. Kaposi sarcoma-associated herpesvirus GPCR (kGPCR) activates proliferative pathways and, when expressed in endothelium in mice, sufficiently induces angiogenic tumor resembling human Kaposi’s sarcoma. IKKε, an IκB kinase (IKK)-related kinase, is implicated in inflammation-driven tumorigenesis. We report here that IKKε is critically required for kGPCR tumorigenesis and links kGPCR to NF-κB activation. Using kGPCR-induced tumor models, we found that IKKε expression was drastically up-regulated in Kaposi sarcoma-like lesions and that loss of IKKε abolished tumor formation. Moreover, kGPCR interacted with and activated IKKε. Activated IKKε promoted NF-κB subunit RelA (also known as p65) phosphorylation, which correlated with NF-κB activation and inflammatory cytokine expression. The robust expression of IKKε and phosphorylated RelA was observed in human Kaposi sarcoma. Finally, a kinase-defective mutant of IKKε effectively abrogated NF-κB activation and tumorigenesis induced by kGPCR. Collectively, our findings uncover a critical IKKε in promoting NF-κB activation and tumorigenesis induced by a viral GPCR.

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confidence: 99%

IKK epsilon kinase is crucial for viral G protein-coupled receptor tumorigenesis

Wang

Zhu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Prospective data are lacking, although a study of HIV infected people in Italy suggested that anti-KSHV antibody titres may be persistently high even before the diagnosis of Kaposi's sarcoma, based on the observation of 21 cases of the tumour (Rezza et al, 1999). Data presented here confirm, on substantially larger numbers of cases, that anti-KSHV antibodies are detectable before the diagnosis of the tumour and that the subsequent risk of Kaposi's sarcoma increases with increasing antibody titres (this is true for latent and lytic antibodies).…”

Section: Discussionmentioning

confidence: 99%

A prospective study of Kaposi's sarcoma-associated herpesvirus and Epstein–Barr virus in adults with human immunodeficiency virus-1

et al. 2006

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Antibody titres against Kaposi's sarcoma associated herpesvirus (KSHV or human herpesvirus 8 (HHV-8)) and Epstein -Barr virus (EBV) were examined in people who subsequently developed Kaposi's sarcoma and non-Hodgkin's lymphoma, within randomised controlled trials of antiretroviral therapy in adults infected with the human immunodeficiency virus-1 (HIV). For each case of Kaposi's sarcoma (n ¼ 189) and each case of non-Hodgkin's lymphoma (n ¼ 67), which developed after randomisation, one control was randomly selected from other trial participants, after matching for age, sex, ethnicity, mode of HIV transmission, type of treatment received and period of follow-up. Using sera taken an average of two and a half years before the diagnosis of cancer, titres of antibodies against KSHV latent (LANA) and lytic (K8.1) antigens and against EBV (VCA) antigens were investigated in relation to subsequent risks of cancer by calculating odds ratios (OR) using conditional logistic regression. Latent antibodies against KSHV were detectable among 38% (72 out of 189) of Kaposi's sarcoma cases and 12% (23 out of 189) of their controls (OR ¼ 4.4, 95% confidence intervals (CI) 2.3 -8.3, Po0.001). The OR for Kaposi's sarcoma increased with increasing antilatent KSHV antibody titre (w 2 1 for trend ¼ 32.2, Po0.001). Lytic antibodies against KSHV were detectable among 33% (61 out of 187) of Kaposi's sarcoma cases and 19% (36 out of 187) of their controls (OR ¼ 2.0, 95% CI 1.2 -3.4, P ¼ 0.003) and the OR for Kaposi's sarcoma increased with increasing antilytic KSHV antibody titre (w 2 1 for trend ¼ 6.2, P ¼ 0.02). Virtually, all cases and controls had anti-EBV antibodies detected and the OR for non-Hodgkin's lymphoma associated with a doubling of the anti-EBV antibody titre was estimated to increase by a multiplicative factor of 1.3 (95% CI 0.9 -1.7, P ¼ 0.1). Kaposi's sarcoma was not associated with antibody levels against EBV (P ¼ 0.4) and non-Hodgkin's lymphoma was not associated with antibodies against KSHV (latent P ¼ 0.3; lytic P ¼ 0.5). Adjustment for CD4 count at the time of sample collection made no material difference to any of the results. In conclusion, among human immunodeficiency virus infected people, high levels of antibodies against KSHV latent and lytic antigens are strongly associated with subsequent risk of Kaposi's sarcoma but not non-Hodgkin's lymphoma. Antibody titre to EBV does not appear to be strongly associated with subsequent risk of Kaposi's sarcoma or non-Hodgkin's lymphoma in HIV infected people.

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“…However, results presented here in relation to KSHV antibody titres are in accord with those reported by Sitas et al (1999) from a case -control study of black South African cancer patients. Furthermore, in a cohort study of HIV-infected men in Europe, Rezza et al (1999) showed that high titres of anti-KSHV antibodies were predictive of the subsequent development of Kaposi's sarcoma among KSHV-infected individuals. These prospective data, together with the fact that the clinical burden of tumour lesions is independent of the titre of anti-KSHV antibodies (Table 1), argue against the possibility that high titres of antibodies against KSHV latent nuclear antigens result from the presence of Kaposi's sarcoma lesions.…”

Section: Discussionmentioning

confidence: 99%

Infection with Kaposi's sarcoma-associated herpesvirus (KSHV) and human immunodeficiency virus (HIV) in relation to the risk and clinical presentation of Kaposi's sarcoma in Uganda

et al. 2003

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Human Herpesvirus 8 Seropositivity and Risk of Kaposi's Sarcoma and Other Acquired Immunodeficiency Syndrome-Related Diseases

Cited by 121 publications

References 36 publications

IKK epsilon kinase is crucial for viral G protein-coupled receptor tumorigenesis

IKK epsilon kinase is crucial for viral G protein-coupled receptor tumorigenesis

A prospective study of Kaposi's sarcoma-associated herpesvirus and Epstein–Barr virus in adults with human immunodeficiency virus-1

Infection with Kaposi's sarcoma-associated herpesvirus (KSHV) and human immunodeficiency virus (HIV) in relation to the risk and clinical presentation of Kaposi's sarcoma in Uganda

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