γ‐Herpesviruses, Epstein–Barr virus (EBV/HHV‐4) and Kaposi's sarcoma‐associated herpesvirus (KSHV/HHV‐8), are involved in human carcinogenesis, particularly in immunocompromised patients. Virus‐associated malignancies are becoming of significant concern for the mortality of long‐lived immunocompromised patients, and therefore, research of advanced strategies for AIDS‐related malignancies is an important field in cancer chemotherapy. Detailed understanding of the EBV and KSHV lifecycle and related cancers at the molecular level is required for novel strategies of molecular‐targeted cancer chemotherapy. The present review gives a simple outline of the functional interactions between KSHV‐ and EBV‐viral gene products and host cell deregulated signaling pathways as possible targets of chemotherapy against AIDS‐related malignancies. (Cancer Sci 2007; 98: 1288–1296)

plied to a wider spectrum of disease processes. In 1994, the U.S. Public Health Service (USPHS) and the So much new data about prevention of opportunistic disease Infectious Diseases Society of America (IDSA) recognized have emerged since 1994 that the USPHS and the IDSA that strategies to reduce the frequency of opportunistic infecdeemed it appropriate to reconvene a working group on 7–8, tions in patients with HIV infection were available but that November 1996 to provide advice about which recommendahealth care providers and patients could benefit from an expert tions needed to be changed. The working group members inreview and a consolidation of the pertinent information into cluded persons from federal agencies, universities, and profesone comprehensive set of guidelines. The resulting USPHS/ sional societies, as well as community health care providers IDSA guidelines were published in 1995 [1–3]; on the basis and patient advocates. Most attention focused on recent data of the volume of requests for copies and the observations related to chemoprophylaxis for disseminated disease due to made by large private and public care providers, these guideMAC and cytomegalovirus (CMV) and fungal infections and lines seem to have provided a reference against which local to immunization against Streptococcus pneumoniae. However, policies could be compared. Since the recommendations were data concerning all the common AIDS-associated pathogens rated on the strength of the supporting evidence, readers were were sought and reviewed. able to assess for themselves which areas to incorporate in As in the earlier guidelines, the factors considered in revising their practices [4]. recommendations were the incidence of disease; the severity Opportunistic infections continue to produce morbidity and of disease in terms of morbidity and mortality; the level of mortality among the estimated 650,000–900,000 persons in immunosuppression at which disease is most likely to occur; the United States who are infected with HIV, especially the the feasibility, efficacy, and cost of preventive measures; the estimated 200,000–250,000 who are severely immunosupimpact of intervention on quality of life; and toxicities, drug pressed, as defined by a CD4/ T lymphocyte count of interactions, and potential for drug resistance. The recommenõ200/mL [2, 5–7]. However, surveillance data indicate that dations have been revised only if full manuscripts detailing the incidence of opportunistic infections has been changing in results were available for review; information from abstracts North America. In HIV-infected men who have sex with men, and oral presentations are mentioned in the preface but were pneumocystosis, toxoplasmosis, fungal infections, and Myconot deemed appropriate for a definitive recommendation if the bacterium avium complex (MAC) disease have decreased in full data could not be reviewed. incidence [5, 8]. More potent antiretroviral drugs and prophyThe recommendations are rated by use of a revised version lactic regimens for opportunistic pathogens seem to be imof the IDSA rating system (tables 1 and 2) [4]. In this system, portant contributors to this decline. However, these decreases a letter rating (A through E) signifies the strength of the recomhave not been observed among HIV-infected injection drug mendation; a Roman numeral (I through III) indicates the qualusers. Thus, more emphasis is needed on providing currently ity of evidence supporting that recommendation. recommended chemoprophylactic agents to all persons with This document is a preface that is followed by disease-specific HIV infection who meet clinical criteria. These surveillance recommendations. In this preface, we review the data that formed data also demonstrate that the incidence of some opportunistic the basis for changing or not changing specific recommendations. infections is not decreasing in either of these populations, indiAfter the revised guidelines were drafted, the document was

miRNAs have emerged as master regulators of cancer-related events. miRNA dysregulation also occurs in Kaposi sarcoma (KS). Exploring the roles of KS-associated miRNAs should help to identify novel angiogenesis and lymphangiogenesis pathways. In the present study, we show that Kaposi sarcoma-associated herpesvirus (KSHV), the etiological agent of KS, induces global miRNA changes in lymphatic endothelial cells (LECs). Specifically, the miR-221/miR-222 cluster is down-regulated, whereas miR-31 is up-regulated. Both latent nuclear antigen (LANA) and Kaposin B repress the expression of the miR-221/miR-222 cluster, which results in an increase of endothelial cell (EC) migration. In contrast, miR-31 stimulates EC migration, so depletion of miR-31 in KSHV-transformed ECs reduces cell motility. Analysis of the putative miRNA targets among KSHV-affected genes showed that ETS2 and ETS1 are the downstream targets of miR-221 and miR-222, respectively. FAT4 is one of the direct targets of miR-31. Overexpression of ETS1 or ETS2 alone is sufficient to induce EC migration, whereas a reduction in FAT4 enhances EC motility. Our results show that KSHV regulates multiple miRNA-mRNA networks to enhance EC motility, which eventually contributes to KS progression by promoting the spread of malignant KS progenitor cells. Targeting KSHV-regulated miRNAs or genes might allow the development of novel therapeutic strategies that induce angiogenesis or allow the treatment of pathogenic (lymph)angiogenesis.

immunoreactivity, respectively. Anti-Bc/-2 staining was performed on formalin-fixed AIDS-KS lesions as described in Materials and Methods.

an important cause of acute confusional state in multiple myeloma

With the advent of massively parallel sequencing, oncogenic viruses in tumours can now be detected in an unbiased and comprehensive manner. Additionally, new viruses or strains can be discovered based on sequence similarity with known viruses. Using this approach, the causative agent for Merkel cell carcinoma was identified. Subsequent studies using data from large collections of tumours have confirmed models built during decades of hypothesis-driven and low-throughput research, and a more detailed and comprehensive description of virus–tumour associations have emerged. Notably, large cohorts and high sequencing depth, in combination with newly developed bioinformatical techniques, have made it possible to rule out several suggested virus–tumour associations with a high degree of confidence. In this review we discuss possibilities, limitations and insights gained from using massively parallel sequencing to characterize tumours with viral content, with emphasis on detection of viral sequences and genomic integration events. This article is part of the themed issue ‘Human oncogenic viruses’.

While Kaposi's sarcoma (KS) is extremely common in homosexual men infected with human immunodeficiency virus (HIV), it is also found in several clinical settings in which HIV infection is absent. Recently, sequences from the genome of a novel member of the herpesvirus family have been identified within KS biopsies in the AIDS-associated form of the disease. The presence of these sequences was sought in 6 cases of HIV-negative KS, including 4 cases of endemic KS from Africa, and was found in 5 of the 6. These findings strengthen the association between infection with this virus and the development of KS and argue against the notion that this association is simply the result of opportunistic superinfection of profoundly immunodeficient hosts.

We recently discovered the Kaposi's sarcoma-associated herpes virus (KSHV/HHV-8) in an uncommon and unusual subset of AIDS-related lymphomas that grow mainly in the body cavities as lymphomatous effusions without an identifiable contiguous tumor mass. The consistent presence of KSHV and certain other distinctive features of these body cavity-based lymphomas suggest that they represent a distinct entity. We tested this hypothesis by investigating 19 malignant lymphomatous effusions occurring in the absence of a contiguous tumor mass for their clinical, morphologic, immunophenotypic, viral, and molecular characteristics, KSHV was present in 15 of 19 lymphomas. All four KSHV-negative lymphomatous effusions exhibited Burkitt or Burkitt-like morphology and c-myc gene rearrangements and, therefore, appeared to be Burkitt-type lymphomas occurring in the body cavities. In contrast, all 15 KSHV-positive lymphomatous effusions exhibited a distinctive morphology bridging large-cell immunoblastic lymphoma and anaplastic large-cell lymphoma, and all 12 cases studied lacked c-myc gene rearrangements. In addition, these lymphomas occurred in men (15/15), frequently but not exclusively in association with HIV infection (13/15), in which homosexuality was a risk factor (13/13), presented initially as a lymphomatous effusion (14/15), remained localized to the body cavity of origin (13/15), expressed CD45 (15/15) and one or more activation-associated antigens (9/10) in the frequent absence of B-cell-associated antigens (11/15), exhibited clonal immunoglobulin gene rearrangements (13/13), contained Epstein-Barr virus (14/15), and lacked bcl-2, bcl-6, ras and p53 gene alterations (13/15). These findings strongly suggest that the KSHV-positive malignant lymphomatous effusions represent a distinct clinicopathologic and biologic entity and should be distinguished from other malignant lymphomas occurring in the body cavities. Therefore, we recommend that these malignant lymphomas be designated primary effusion lymphomas (PEL), rather than body cavity-based lymphomas, since this term describes them more accurately and avoids their confusion with other malignant lymphomas that occur in the body cavities. We further recommend that these PEL be considered for inclusion as a new entity in the Revised European-American Lymphoma Classification.

We performed a cross-sectional study to estimate the prevalence of 2 gamma-2-herpesviruses, rhesus rhadinovirus (RRV) and retroperitoneal fibromatosis herpesvirus (RFHV), in breeding colonies of rhesus macaques. Of 90 animals selected for sampling, 73 (81%) were positive for RRV, which was detected only in blood in 22 (24%), only in saliva in 15 (16%), and in both blood and saliva in 36 (40%). Detection of RRV DNA in blood and saliva was significantly higher in animals younger than 2 y. In comparison, RFHV was detected in 40 (44%) of the 90 animals: only in blood in 5 (6%), only in saliva in 26 (29%), and in both blood and saliva in 9 (10%). Dual infection was detected in 38 (42%) animals; RFHV was only detected in coinfections. The mean RRV genome copy number in blood was significantly higher than that for RFHV. Age was a significant predictor of RRV copy number in blood and RFHV copy number in saliva. Of the 90 animals, 88 (98%) were positive for rhadinoviral antibodies on an immunofluorescent assay. Both RRV and RFHV are highly endemic in socially housed breeding colonies of rhesus macaques, and their patterns of infection are similar to that for the betaherpesvirus rhesus cytomegalovirus.

We linked records of 83,434 AIDS cases reported to AIDS registries through 1990 to cancer registry records during times when overlap in registration existed. Of 8,496 Kaposi's‐sarcoma (KS) cases meeting enrollment criteria, 1,045 occurred semesters 2 through 4 (6 through 23 months) after another AIDS‐defining illness. KS risk in this period after AIDS declined steadily over the 1980s. Adjusting for age, gender, ethnic origin and calendar time period, we found the relative risk (RR) of KS to be 106,000 for homo/bisexual men with AIDS and 13,000 for other men with AIDS. Risk was highest for homo/bisexual men between 30 and 39 years old and among 20‐ to 29‐year‐old non‐homo/bisexual men. The RR in black men was approximately half that reported in white men among homo‐bisexual men and others. Between the second and fourth semester after AIDS, the ratio of RR of KS to that of non‐AIDS‐related cancers increased 1.5‐fold. In a similar analysis, there were 335 non‐Hodgkin's lymphoma (NHL) cases in semesters 2 through 4 after AIDS. The overall risk was elevated 283‐fold in homo/bisexual men and the RR ratio increased 1.8‐fold between semester 2 and 4 after AIDS. In summary, the risk of KS following another AlDS‐defining illness is strikingly high, more in white men than in black men, and the risks of KS and, especially, NHL appear to increase with time from AIDS. (This article is a US Government work and, as such, is in the public domain in the United States of America.) © 1996 Wiley‐Liss, Inc.

We have developed a computational subtraction approach to detect microbial causes for putative infectious diseases by filtering a set of human tissue–derived sequences against the human genome. We demonstrate the potential of this method by identifying sequences from known pathogens in established expressed–sequence tag libraries.

We have cloned and characterized the entire DNA polymerase gene and flanking regions from Kaposi's sarcoma-associated herpesvirus (KSHV) and two closely related macaque homologs of KSHV, retroperitoneal fibromatosis-associated herpesvirus-Macaca nemestrina (RFHVMn) and -Macaca mulatta (RFHVMm). We have also identified and partially characterized the corresponding genomic region of another KSHV-like herpesvirus, provisionally named “M. nemestrina rhadinovirus type 2 (MneRV-2),” with close similarity to rhesus rhadinovirus (RRV). A sequence comparison of these four macaque viruses and two KSHV-like gammaherpesviruses recently identified in African green monkeys, Chlorocebus rhadinovirus types 1 and 2 (ChRV-1 and ChRV-2) reveals the presence of two distinct lineages of KSHV-like rhadinoviruses in Old World primates. The first rhadinovirus lineage consists of KSHV and its closely related homologs RFHVMn, RFHVMm, and ChRV-1, while the second more distantly related lineage consists of RRV, MneRV-2, and ChRV-2. Our findings raise the possibility of the existence of another human KSHV-like herpesvirus belonging to the second rhadinovirus lineage.

We examined human herpesvirus 8 (HHV-8) seroprevalence and seroincidence among 245 homosexual men from New York City (NYC) and Washington, DC (DC) who have been followed since 1982. An immunofluorescence assay measured antibodies to a latent HHV-8 nuclear antigen. Seroprevalence was 20.4% in 1982; seroincidence was approximately 15%/year during 1982-1983 but fell sharply thereafter. NYC men had a higher seroprevalence (odds ratio, 3.43; P<.001) and seroincidence (rate ratio, 2.13; P=.01) than DC men. Risk of Kaposi's sarcoma (KS) was increased in seropositive men (adjusted relative hazard, 3.58; P=.02). Among men who were seropositive for both human immunodeficiency virus type 1 and HHV-8, the 10-year cumulative risk of KS was 39%; time from coinfection to KS diagnosis ranged from 15 to 154 months (median, 63.5 months). This study shows an epidemic of HHV-8 among US homosexual men in the early 1980s that was associated with a high risk of developing KS.

Vol. 203, No. 5, May 15, 2006 1235–1247 www.jem.org/cgi/doi/10.1084/jem.20051921 1235 Work over the past 30 yr has resulted in a greater understanding of the biology and therapeutic application of human stem cells in human malignancies. The use of stem cell transplantation is an important tool in the treatment of several hematologic (1) and nonhematologic (2, 3) malignancies. In contrast, several recent studies have suggested that stem and progenitor cells may be direct cellular targets of the genetic alterations leading to tumor formation as well as important contributors to the maintenance of human cancers (4–6). In addition, other recent studies have altered the perception of the stromal cells that surround epithelial tumors from being innocent bystanders in the neoplastic process to being a cell type that actively promotes the growth of the adjacent transformed cells (7–11). However, the eff ect of human mesenchymal stem cells (MSCs), the stromal progenitor stem cells found within the bone marrow, on the growth of human tumors is not well understood. The cell population known as MSCs are usually isolated from the mononuclear fraction of a bone marrow aspirate, which is then depleted of CD45+ cells and subsequently isolated as the cell population that adheres to plastic tissue culture dishes (12). MSCs can proliferate for many passages in culture and have the ability to give rise to several diff erentiated cell types (13). MSCs have several properties that make them an attractive choice as a cell therapeutic Human mesenchymal stem cells exert potent antitumorigenic eff ects in a model of Kaposi’s sarcoma

Viruses use a surprising diversity of approaches to hijack G-protein-coupled receptors and harness their activated intracellular signalling pathways. All of these approaches ultimately function to ensure viral replicative success and often contribute to their pathogenesis. Indeed, a single virus might deploy a repertoire of these strategies to regulate key intracellular survival, proliferative and chemotactic pathways. Understanding the contribution of these biochemical routes to viral pathogenesis might facilitate the development of effective target-specific therapeutic strategies against viral diseases.

Viruses that maintain their genomes as extrachromosomal circular DNA molecules and establish infection in actively dividing cells must ensure retention of their genomes within the nuclear envelope in order to prevent genome loss. The loss of nuclear membrane integrity during mitosis dictates that paired host cell chromosomes are captured and organized by the mitotic spindle apparatus before segregation to daughter cells. This prevents inaccurate chromosomal segregation and loss of genetic material. A similar mechanism may also exist for the nuclear retention of extrachromosomal viral genomes or episomes during mitosis, particularly for genomes maintained at a low copy number in latent infections. It has been heavily debated whether such a mechanism exists and to what extent this mechanism is conserved among diverse viruses. Research over the last two decades has provided a wealth of information regarding the mechanisms by which specific tumour viruses evade mitotic and DNA damage checkpoints. Here, we discuss the similarities and differences in how specific viruses tether episomal genomes to host cell chromosomes during mitosis to ensure long-term persistence.

Viruses are the smallest known microbes, yet they cause the most significant losses in human health. Most of the time, the best-known cure for viruses is the innate immunological defense system of the host; otherwise, the initial prevention of viral infection is the only alternative. Therefore, diagnosis is the primary strategy toward the overarching goal of virus control and elimination. The introduction of a new class of nanoscale materials with multiple unique properties and functions has sparked a series of breakthrough applications. Gold nanoparticles (AuNPs) are widely reported to guide an impressive resurgence in biomedical and diagnostic applications. Here, we review the applications of AuNPs in virus testing and detection. The developed AuNP-based detection techniques are reported for various groups of clinically relevant viruses with a special focus on the applied types of bio-AuNP hybrid structures, virus detection targets, and assay modalities and formats. We pay particular attention to highlighting the functional role and activity of each core Au nanostructure and the resultant detection improvements in terms of sensitivity, detection range, and time. In addition, we provide a general summary of the contributions of AuNPs to the mainstream methods of virus detection, technical measures, and recommendations required in guidance toward commercial in-field applications.

Viruses are the most important cause of infections and a major source of mortality in Kidney Transplant Recipients (KTRs). These patients may acquire viral infections through exogenous routes including community exposure, donor organs, and blood products or by endogenous reactivation of latent viruses. Beside major opportunistic infections due to CMV and EBV and viral hepatitis B and C, several viral diseases have recently emerged in KTRs. New medical practices or technologies, implementation of new diagnostic tools, and improved medical information have contributed to the emergence of these viral diseases in this special population.

Viral integration plays an important role in the development of malignant diseases. Viruses differ in preferred integration site and flanking sequence. Viral integration sites (VIS) have been found next to oncogenes and common fragile sites. Understanding the typical DNA features near VIS is useful for the identification of potential oncogenes, prediction of malignant disease development and assessing the probability of malignant transformation in gene therapy. Therefore, we have built a database of human disease-related VIS (Dr.VIS, http://www.scbit.org/dbmi/drvis) to collect and maintain human disease-related VIS data, including characteristics of the malignant disease, chromosome region, genomic position and viral–host junction sequence. The current build of Dr.VIS covers about 600 natural VIS of 5 oncogenic viruses representing 11 diseases. Among them, about 200 VIS have viral–host junction sequence.

Viral Interleukin-6 (vIL-6) is encoded by Human herpes virus 8 (HHV8), also known as Kaposi's sarcoma (KS)-associated herpes virus (KSHV). HHV8 infection is found in patients with KS, primary effusion lymphoma (PEL) and plasma cell-type of multicentric Castleman's disease (MCD), with a high incidence observed in HIV infected individuals. vIL-6 shares about 25% identity with its human counterpart. Human IL-6 (hIL-6) binds to the human IL-6 receptor (hIL-6R) and the hIL-6/hIL-6R complex associates with the signaling receptor subunit gp130. Upon dimerization of gp130 intracellular signaling is initiated. All cells in the body express gp130 but only some cell types express the hIL-6R. Human IL-6 does not stimulate cells, which do not express hIL-6R. However, a naturally occurring soluble form of the hIL-6R (shIL-6R) can bind hIL-6 and the complex of hIL-6/shIL-6R can stimulate cells, which only express gp130 but no hIL-6R. This process, which has been named trans-signaling, leads to a dramatic increase in the spectrum of hIL-6 target cells during inflammation and cancer. vIL-6, in contrast to hIL-6, can directly bind to and activate gp130 without the need of the hIL-6R. Therefore, at least in theory, vIL-6 can stimulate every cell in the human body. This review highlights the properties of vIL-6 regarding structural features, implications for pathophysiology, and strategies of neutralization. Furthermore, mechanisms of activation of gp130 by hIL-6, vIL-6, and by forced dimerization will be discussed.