ROLE OF HHV-8 VIRAL PARAMETERS AND KIR/HLA COMPLEXES ON THE DEVELOPMENT OF CLASSIC AND EPIDEMIC KAPOSI'S SARCOMA.

Kaposi’s sarcoma (KS) is a rare vascular tumor of the skin related to Human Herpesvirus 8 (HHV-8) infection. Based on clinical and pathological characteristics, KS is divided in four different forms: classic KS (cKS), epidemic (or AIDSassociated) KS, endemic KS and iatrogenic KS. Although the link between HHV-8 and disease has been demonstrated, it is important to note that the HHV-8 infection is necessary but not sufficient to develop the disease: many important aspects remain to be elucidated, regarding both viral factors, as presence of antibody anti-HHV-8, viral transmission and pathogenic potential of different viral genotypes, and host predisposition to tumor development, different from person to person. Natural killer cells are central components of the innate immune response against viral infection and tumor growth: the modulation of their activity is a complex and multi factorial phenomenon triggered by the binding of inhibitory or activating killer cell immunoglobulin-like receptors (KIRs) to class I human leukocyte antigens (HLAs). For these reasons, the objective of this thesis is to verify whether the development of cKS and epidemic KS is related with particular HHV-8 viral parameters (viral load, genotype) or with particular host KIR/HLA receptor/ligand genotype, comparing cKS and epidemic KS patients with the appropriate control groups. Regarding the viral parameters, anti-HHV-8 antibodies were detected in all (100%) cKS patients, and in 80% of epidemic KS patients, whereas they are present in 50% of HIV+ healthy individuals and in 10% of HIVhealthy donors only (p<0.0001). Moreover, when the HHV-8 genotypes were analyzed, A subtype was significantly more frequently isolated in cKS patients with fast progression of the disease (63.6% vs 23.1%), whereas C subtype in individuals with slow progression (76.9% vs 36.4%; p=0.003). Regarding the host genetic aspects, activating KIRs, toghether with their HLA ligands, were more frequent in cKS and epidemic KS compared to non-KS subjects, regardless of the presence or absence of HHV-8 or HIV infection. Considering the activating KIR one by one, the KIR2DS2 gene was significantly prevalent in both cKS and epidemic KS patients (p=0.02 for both), whereas KIR2DS1 and KIR3DS1 genes were more prevalent in cKS patients (p=0.02 and p=0.04 respectively). Moreover, considering the KIR/HLA complexes, the activating KIR2DS1/C2 genotype was positively associated with cKS development (p=0.01). Finally, the inhibitory KIR distribution, as well as the HLA ligand distribution alone, did not reveal any statistical association with cKS or epidemic KS. In conclusion, this study shows that 1) the A genotype of HHV-8 is associated with worst clinical parameters of KS, including faster progression, 2) that a KIR/HLA “activating milieu” is present in cKS and epidemic KS and that such milieu may be a risk factor for the development of the tumor.