Kaposi's Sarcoma-Associated Herpesvirus, the Etiological Agent of All Epidemiological Forms of Kaposi's Sarcoma.

Kaposi's sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8 (HHV-8), is an oncogenic virus belonging to the Herpesviridae family. The viral particle is composed of a double-stranded DNA harboring 90 open reading frames, incorporated in an icosahedral capsid and enveloped. The viral cycle is divided in the following two states: a short lytic phase, and a latency phase that leads to a persistent infection in target cells and the expression of a small number of genes, including LANA-1, v-FLIP and v-cyclin. The seroprevalence and risk factors of infection differ around the world, and saliva seems to play a major role in viral transmission. KSHV is found in all epidemiological forms of Kaposi's sarcoma including classic, endemic, iatrogenic, epidemic and non-epidemic forms. In a Kaposi's sarcoma lesion, KSHV is mainly in a latent state; however, a small proportion of viral particles (<5%) are in a replicative state and are reported to be potentially involved in the proliferation of neighboring cells, suggesting they have crucial roles in the process of tumorigenesis. KSHV encodes oncogenic proteins (LANA-1, v-FLIP, v-cyclin, v-GPCR, v-IL6, v-CCL, v-MIP, v-IRF, etc.) that can modulate cellular pathways in order to induce the characteristics found in all cancer, including the inhibition of apoptosis, cells' proliferation stimulation, angiogenesis, inflammation and immune escape, and, therefore, are involved in the development of Kaposi's sarcoma.

Latently KSHV-Infected Cells Promote Further Establishment of Latency upon Superinfection with KSHV.

Kaposi's sarcoma-associated herpesvirus (KSHV) is a cancer-related virus which engages in two forms of infection: latent and lytic. Latent infection allows the virus to establish long-term persistent infection, whereas the lytic cycle is needed for the maintenance of the viral reservoir and for virus spread. By using recombinant KSHV viruses encoding mNeonGreen and mCherry fluorescent proteins, we show that various cell types that are latently-infected with KSHV can be superinfected, and that the new incoming viruses establish latent infection. Moreover, we show that latency establishment is enhanced in superinfected cells compared to primary infected ones. Further analysis revealed that cells that ectopically express the major latency protein of KSHV, LANA-1, prior to and during infection exhibit enhanced establishment of latency, but not cells expressing LANA-1 fragments. This observation supports the notion that the expression level of LANA-1 following infection determines the efficiency of latency establishment and avoids loss of viral genomes. These findings imply that a host can be infected with more than a single viral genome and that superinfection may support the maintenance of long-term latency.

Pathological Features of Kaposi's Sarcoma-Associated Herpesvirus Infection.

Kaposi's sarcoma-associated herpesvirus (KSHV, human herpesvirus 8, or HHV-8) was firstly discovered in Kaposi's sarcoma tissue derived from patients with acquired immune deficiency syndrome. KSHV infection is associated with malignancies and certain inflammatory conditions. In addition to Kaposi's sarcoma, KSHV has been detected in primary effusion lymphoma, KSHV-associated lymphoma, and some cases of multicentric Castleman disease (MCD). Recently, KSHV inflammatory cytokine syndrome (KICS) was also defined as a KSHV-associated disease. In KSHV-associated malignancies, such as Kaposi's sarcoma and lymphoma, KSHV latently infects almost all tumor cells, and lytic proteins are rarely expressed. A high titer of KSHV is detected in the sera of patients with MCD and KICS, and the expression of lytic proteins such as ORF50, vIL-6, and vMIP-I and vMIP-II is frequently observed in the lesions of patients with these diseases. Immunohistochemistry of LANA-1 is an important diagnostic tool for KSHV infection. However, much of the pathogenesis of KSHV remains to be elucidated, especially regarding oncogenesis. Some viral proteins have been shown to have transforming activity in mammalian cells; however, these proteins are not expressed in latently KSHV-infected cells. KSHV encodes homologs of cellular proteins in its genome such as cyclin D, G-protein coupled protein, interleukin-6, and macrophage inflammatory protein-1 and -2. Molecular mimicry by these viral proteins may contribute to the establishment of microenvironments suitable for tumor growth. In this review, the virus pathogenesis is discussed based on pathological and experimental findings and clinical aspects.

Cyclooxygenase-2-prostaglandin E2-eicosanoid receptor inflammatory axis: a key player in Kaposi's sarcoma-associated herpes virus associated malignancies.

The role of cyclooxygenase-2 (COX-2), its lipid metabolite prostaglandin E2 (PGE2), and Eicosanoid (EP) receptors (EP; 1-4) underlying the proinflammatory mechanistic aspects of Burkitt's lymphoma, nasopharyngeal carcinoma, cervical cancer, prostate cancer, colon cancer, and Kaposi's sarcoma (KS) is an active area of investigation. The tumorigenic potential of COX-2 and PGE2 through EP receptors forms the mechanistic context underlying the chemotherapeutic potential of nonsteroidal anti-inflammatory drugs (NSAIDs). Although role of the COX-2 is described in several viral associated malignancies, the biological significance of the COX-2/PGE2/EP receptor inflammatory axis is extensively studied only in Kaposi's sarcoma-associated herpes virus (KSHV/HHV-8) associated malignancies such as KS, a multifocal endothelial cell tumor and primary effusion lymphoma (PEL), a B cell-proliferative disorder. The purpose of this review is to summarize the salient findings delineating the molecular mechanisms downstream of COX-2 involving PGE2 secretion and its autocrine and paracrine interactions with EP receptors (EP1-4), COX-2/PGE2/EP receptor signaling regulating KSHV pathogenesis and latency. KSHV infection induces COX-2, PGE2 secretion, and EP receptor activation. The resulting signal cascades modulate the expression of KSHV latency genes (latency associated nuclear antigen-1 [LANA-1] and viral-Fas (TNFRSF6)-associated via death domain like interferon converting enzyme-like- inhibitory protein [vFLIP]). vFLIP was also shown to be crucial for the maintenance of COX-2 activation. The mutually interdependent interactions between viral proteins (LANA-1/vFLIP) and COX-2/PGE2/EP receptors was shown to play key roles in the biological mechanisms involved in KS and PEL pathogenesis such as blockage of apoptosis, cell cycle regulation, transformation, proliferation, angiogenesis, adhesion, invasion, and immune-suppression. Understanding the COX-2/PGE2/EP axis is very important to develop new safer and specific therapeutic modalities for KS and PEL. In addition to COX-2 being a therapeutic target, EP receptors represent ideal targets for pharmacologic agents as PGE2 analogues and their blockers/antagonists possess antineoplastic activity, without the reported gastrointestinal and cardiovascular toxicity observed with few a NSAIDs.

Pathology of Kaposi's Sarcoma-Associated Herpesvirus Infection.

Kaposi's sarcoma-associated herpesvirus (KSHV; human herpesvirus 8) is a human herpesvirus, classified as a gamma-herpesvirus. KSHV is detected in Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and some cases of multicentric Castleman's disease (MCD). Similar to other herpes viruses, there are two phases of infection, latent and lytic. In KSHV-associated malignancies such as KS and PEL, KSHV latently infects almost all tumor cells. Quantitative PCR analysis revealed that each tumor cell contains one copy of KSHV in KS lesions. The oncogenesis by KSHV has remained unclear. Latency-associated nuclear antigen (LANA)-1 plays an important role in the pathogenesis of KSHV-associated malignancies through inhibition of apoptosis and maintenance of latency. Because all KSHV-infected cells express LANA-1, LANA-1 immunohistochemistry is a useful tool for diagnosis of KSHV infection. KSHV encodes some homologs of cellular proteins including cell-cycle regulators, cytokines, and chemokines, such as cyclin D, G-protein-coupled protein, interleukin-6, and macrophage inflammatory protein-1 and -2. These viral proteins mimic or disrupt host cytokine signals, resulting in microenvironments amenable to tumor growth. Lytic infection is frequently seen in MCD tissues, suggesting a different pathogenesis from KS and lymphoma.

[pORF73 functions in the latency of rhadinoviruses]. / Les rôles de la protéine codée par le cadre de lecture ouvert 73 (ORF73) dans la latence des rhadinovirus.

The expression product of the ORF73 (pORF73) is a protein essential for latency of rhadinoviruses, a viral genus related to the Gammaherpesvirinae. pORF73 mediates the tethering of the viral genomes to cellular chromosomes enabling transmission of viral episome to daughter cells. Moreover, pORF73 modulates viral and cellular processes to generate an environment favourable to latency. The goal of this review is to summarize the knowledge available to date on pORF73. This review will focus on the prototype pORF73 encoded by Human Herpes Virus 8 (HHV-8) but also on the orthologues that have been studied so far. It highlights the diversity of pORF73 orthologue functions in the latency of rhadinoviruses.