Kaposi's Sarcoma Virus Research Articles

Herpesviruses and human papillomaviruses in saliva and biopsies of patients with orofacial tumors

ObjectivesTo determine the prevalence and association of HPV and Herpesviruses in saliva and tissue samples of patients with orofacial tumors. MethodsBiopsies of tumors were done, and saliva samples were collected from patients with orofacial tumors for the determination of viruses using nested multiplex PCR. Independent variables were sex, age, comorbidities, tumor stage, and length of stay. Outcome variables were the presence or absence of herpesviruses and HPV. Descriptive summaries and inferential statistics were done. ResultsA hundred patients were included in the study. Prevalence of herpesviruses and HPV were 17.6 % and 57.0 % in tumors, and 48.3 % and 60.0 % in the saliva of patients respectively. Herpesviruses detected included EBV (21.3 %), HHV-7 (11.2 %), CMV (6.7 %), HSV-1 (5.1 %), HSV-2 (1.1 %), VZV (1.1 %), and Kaposi sarcoma virus (0.6 %). The most prevalent HPV genotypes were HPV-42 (29 %), HPV-43 (22.7 %), HPV-52 (22.2 %), HPV-39 (18.8 %), and HPV-18 (9.1 %). The odds of EBV being detected in malignant orofacial tumors were 2 times that of benign orofacial tumors. HPV DNA in the saliva of patients with orofacial tumors was 69.7 %, compared to 18.2 % of the control sample (p < 0.001). The median length of stay for all participants was 6.5 days, those associated with viruses stayed longer. ConclusionThere was a high prevalence of Herpesviruses and HPV in saliva and tumor samples of patients with orofacial tumors, signalling some potential for more work to be done in this area.

Comprehensive Analysis of the Tegument Proteins Involved in Capsid Transport and Virion Morphogenesis of Alpha, Beta and Gamma Herpesviruses.

Herpesviruses are enveloped and have an amorphous protein layer surrounding the capsid, which is termed the tegument. Tegument proteins perform critical functions throughout the viral life cycle. This review provides a comprehensive and comparative analysis of the roles of specific tegument proteins in capsid transport and virion morphogenesis of selected, well-studied prototypes of each of the three subfamilies of Herpesviridae i.e., human herpesvirus-1/herpes simplex virus-1 (Alphaherpesvirinae), human herpesvirus-5/cytomegalovirus (Betaherpesvirinae) and human herpesvirus -8/Kaposi's sarcomavirus (Gammaherpesvirinae). Most of the current knowledge is based on alpha herpesviruses, in particular HSV-1. While some tegument proteins are released into the cytoplasm after virus entry, several tegument proteins remain associated with the capsid and are responsible for transport to and docking at the nucleus. After replication and capsid formation, the capsid is enveloped at the nuclear membrane, which is referred to as primary envelopment, followed by de-envelopment and release into the cytoplasm. This requires involvement of at least three tegument proteins. Subsequently, multiple interactions between tegument proteins and capsid proteins, other tegument proteins and glycoproteins are required for assembly of the virus particles and envelopment at the Golgi, with certain tegument proteins acting as the central hub for these interactions. Some redundancy in these interactions ensures appropriate morphogenesis.

Lymphomas with plasmablastic features: a report of the lymphoma workshop of the 20th meeting of the European Association for Haematopathology.

Lymphomas with plasmablastic features are a heterogeneous group of aggressive and mostly uncommon neoplasms of varied aetiologies, presenting in immunocompetent individuals as well as in immunodeficiency, associated with EBV and Kaposi sarcoma virus infections, and some as progression from indolent B-cell lymphomas. They show overlapping diagnostic features and pose a differential diagnosis with other aggressive B-cell lymphomas that can downregulate the B-cell expression programme. The spectrum of rare reactive proliferations and all lymphomas defined by plasmablastic features, together with an expanding range of poorly characterised, uncommon conditions at the interface between reactive lymphoid proliferations and neoplasia submitted to the session V of the 20th European Association for Haematopathology/Society for Hematopathology lymphoma workshop are summarised and discussed in this paper.

Molecular epidemiology of Kaposi sarcoma virus in Spain.

Since human herpesvirus 8 (HHV-8) infection may be underestimated and HHV-8 subtype circulation in Spain remains unknown, a molecular epidemiologic study is highly desirable. This study aimed to analyse HHV-8 subtype diversity and their distribution in Spain. The study included 142 HHV-8 infected patients. A nested PCR was developed in order to permit Sanger sequencing of HHV-8 K1 ORF directly from clinical samples received at the CNM from 2013 to 2021. Phylogenetic characterization was performed. Genotypes A and C comprised 55.6% and 42.3% of strains. Regarding subtypes, 25.4% of strains were C3, 19.7% were A3, 14.1% were A5, and C2, A1, A4, C1, A2, C7 were 11.3%, 11.3%, 8.5%, 4.2%, 2.1% and 1.4%, respectively. Subtype E1, E2 and B1 were found in only one patient each (0.7%). The Madrid region accounted for 52.1% of patients and showed a significantly different subtype distribution compared to the others (P = 0.018). Subtypes B1, E1, and E2 were observed to appear sporadically, although overall genotypes A and subtype C3 remained the most frequent and unwavering. Subtype A3 presented the highest diversity as displayed by the highest number of clusters in phylogenetic analysis. Non-significant differences in viral loads between genotypes were found, but significantly higher viral loads in subtype C2 compared to subtype C3 was found, while no significant subtype differences were observed between subtypes within genotype A. Infections with HHV-8 were detected in 94 (66.2%) patients without KS and compared to patients with KS non-significant differences in subtype distribution were found. Subtype prevalence and regional distribution followed a similar pattern compared to other western European countries. Our study is the first to report HHV-8 subtypes E1 and E2 circulating in Europe that might be reflective of migration of population from Caribbean countries. Our study suggests that infection by HHV-8 is underestimated, and wider screening should be recommended for risk groups.

The Influence of Oncogenic Viruses in Renal Carcinogenesis: Pros and Cons.

Viral infections are major contributors to the global cancer burden. Recent advances have revealed that known oncogenic viruses promote carcinogenesis through shared host cell targets and pathways. The aim of this review is to point out the connection between several oncogenic viruses from the Polyomaviridae, Herpesviridae and Flaviviridae families and renal carcinogenesis, highlighting their involvement in the carcinogenic mechanism. We performed a systematic search of the PubMed and EMBASE databases, which was carried out for all the published studies on RCC in the last 10 years, using the following search algorithm: renal cell carcinoma (RCC) and urothelial carcinoma, and oncogenic viruses (BKPyV, EBV, HCV, HPV and Kaposi Sarcoma Virus), RCC and biomarkers, immunohistochemistry (IHC). Our analysis included studies that were published in English from the 1st of January 2012 to the 1st of May 2022 and that described and analyzed the assays used for the detection of oncogenic viruses in RCC and urothelial carcinoma. The virus most frequently associated with RCC was BKPyV. This review of the literature will help to understand the pathogenic mechanism of the main type of renal malignancy and whether the viral etiology can be confirmed, at a minimum, as a co-factor. In consequence, these data can contribute to the development of new therapeutic strategies. A virus-induced tumor could be efficiently prevented by vaccination or treatment with oncolytic viral therapy and/or by targeted therapy.

Epstein-Barr Virus, But Not Human Papillomavirus, Is Associated With Preinvasive and Invasive Ocular Surface Squamous Neoplasias in Zambian Patients.

BackgroundThe etiopathogenesis of ocular surface squamous neoplasia (OSSN) is not fully understood. We assessed the frequency of oncogenic viruses in OSSN by immunohistochemistry (IHC) and polymerase chain reaction (PCR) for human papillomavirus (HPV), Epstein–Barr virus (EBV), Merkel cell polyomavirus (MCPyV), Kaposi sarcoma virus, and adenovirus. Cases from Zambia were prospectively enrolled using a cross-sectional study design between November 2017 and March 2020.MethodsDemographic and clinical data [age, sex, HIV status, antiretroviral therapy (ART) history, CD4 count, plasma viral load] and tumor biopsies were collected from 243 consenting patients. Tumor samples were bisected, and half was used for DNA isolation, while the other half was formalin fixed and paraffin embedded (FFPE) for histopathology analysis. The expressions of latent EBV nuclear antigen 1 (EBNA1), CDKN2A/p16INK4A (p16), and MCPyV large T-antigen (LT) were tested by IHC. Multiplex PCR was used to detect 16 HPV genotypes and four other DNA tumor viruses [Kaposi’s sarcoma-associated herpesvirus (KSHV), EBV, MCPyV, and adenovirus]. Relationships between HIV status, viral DNA and protein expression, and tumor grades were determined by statistical analysis.ResultsOSSN tumors from patients were 29.6% preinvasive and 70.4% invasive. Patients presented with unilateral tumors that were 70.4% late stage (T3/T4). OSSN patients were HIV positive (72.8%). IHC on 243 FFPE biopsies resulted in the detection of EBNA1 (EBV), p16 high-risk HPV (HR-HPV), and MCPyV LT expression in 89.0%, 4.9%, and 0.0%, respectively. EBNA1 was expressed in all grades of preinvasive [cornea–conjunctiva intraepithelial neoplasia (CIN)1, 100%; CIN2, 85.7%; CIN3, 95.8%; and carcinoma in situ (CIS), 83.8%] and in invasive (89.2%) OSSN. PCR on 178 samples detected EBV, HR-HPV, and MCPyV in 80.3%, 9.0%, and 13.5% of tumors, respectively. EBV was detected in all grades of preinvasive and invasive OSSN. EBV detection was associated with high HIV viral loads (p = 0.022). HR-HPV was detected in 0.0% CIN1, 0.0% CIN2, 5.6% CIN3, 13.0% CIS, and 7.0% invasive OSSN.ConclusionsOur findings of EBV DNA and EBNA1 protein in all the grades of preinvasive and especially invasive OSSN are consistent with a potential causal role for EBV in OSSN. A role of HPV in OSSN was not clearly established in this study.

Identifying New Immune Response Dynamics in Virus-Associated Cancers

Identifying New Immune Response Dynamics in Virus-Associated Cancers

Dissecting the mechanism of host shutoff by SARS coronavirus

Down regulation of host gene expression during viral infection, known as host shutoff, involves destabilization of host mRNA. Several viruses, including Kaposi's sarcoma virus, Epstein B virus, severe acute respiratory syndrome coronavirus (SARS CoV) and Middle Eastern respiratory syndrome coronavirus inhibit host gene expression by stalling the ribosome on mRNA and subsequently cleaving and degrading host mRNA. In SARS‐CoV, nsp1 is the key factor in virus‐induced down‐regulation of host gene expression. In infected cells, nsp1 engages in a multi‐pronged mechanism to inhibit host gene expression by binding to the 40S ribosomal subunit to stall further ribosome assembly and inducing endonucleolytic cleavage and degradation of host mRNAs. We identified a previously undetected mechanism by which nsp1 exploits the nuclear pore complex and disrupts nuclear‐cytoplasmic transport of biomolecules. Using quantitative proteomics we identified members of the nuclear pore complex from nsp1‐associated protein assembly. Expression of nsp1 in HEK cells disrupts Nup93 localization around the nuclear envelope without triggering proteolytic degradation of the protein while other nucleoporins and the nuclear lamina remain unperturbed, suggesting significant alteration of the nuclear pore complex in the presence of nsp1. Furthermore, Nup93 reconvenes to the nuclear pore when nsp1 is removed. Consistent with its role in host shutoff, nsp1 alters the nuclear‐cytoplasmic distribution of a RNA binding protein, nucleolin. Our results suggest that nsp1 alone can regulate multiple steps of gene expression including nuclear‐cytoplasmic transport.Support or Funding InformationSC INBRE Bioinformatics Pilot Project AwardSCICUThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

In vitro toxicity and efficacy of verdinexor, an exportin 1 inhibitor, on opportunistic viruses affecting immunocompromised individuals.

Infection of immunocompromised individuals with normally benign opportunistic viruses is a major health burden globally. Infections with viruses such as Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), Kaposi’s sarcoma virus (KSHV), adenoviruses (AdV), BK virus (BKPyV), John Cunningham virus (JCPyV), and human papillomavirus (HPV) are significant concerns for the immunocompromised, including when these viruses exist as a co-infection with human immunodeficiency virus (HIV). These viral infections are more complicated in patients with a weakened immune system, and often manifest as malignancies resulting in significant morbidity and mortality. Vaccination is not an attractive option for these immune compromised individuals due to defects in their adaptive immune response. Verdinexor is part of a novel class of small molecules known as SINE (Selective Inhibitor of Nuclear Export) compounds. These small molecules demonstrate specificity for the nuclear export protein XPO1, to which they bind and block function, resulting in sequestration of XPO1-dependent proteins in the nucleus of the cell. In antiviral screening, verdinexor demonstrated varying levels of efficacy against all of the aforementioned viruses including previously with HIV. Studies by other labs have discussed likely mechanisms of action for verdinexor (ie. XPO1-dependence) against each virus. GLP toxicology studies suggest that anti-viral activity can be achieved at a tolerable dose range, based on the safety profile of a previous phase 1 clinical trial of verdinexor in healthy human volunteers. Taken together, these results indicate verdinexor has the potential to be a broad spectrum antiviral for immunocompromised subjects for which vaccination is a poor option.

The implication of CRISPR/Cas9 genome editing technology in combating human oncoviruses.

It is evidenced that 20% of all tumors in humans are caused by oncoviruses, including human papilloma viruses, Epstein-Barr virus, Kaposi sarcoma virus, human polyomaviruses, human T-lymphotrophic virus-1, and hepatitis B and C viruses. Human immunodeficiency virus is also involved in carcinogenesis, although not directly, but by facilitating the infection of many oncoviruses through compromising the immune system. Being intracellular parasites with the property of establishing latency and integrating into the host genome, these viruses are a therapeutic challenge for biomedical researchers. Therefore, strategies able to target nucleotide sequences within episomal or integrated viral genomes are of prime importance in antiviral or anticancerous armamentarium. Recently, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) has emerged as a powerful genome editing tool. Standing out as a precise and efficient oncoviruses method, it has been extensively applied in recent experimental ventures in the field of molecular medicine, particularly in combating infections including tumor inducing viruses. This review is aimed at collating the experimental and clinical advances in CRISPR/Cas9 technology in terms of its applications against oncoviruses. Primarily, it will focus on the application of CRISPR/Cas9 in combating tumor viruses, types of mechanisms targeted, and the significant outcomes till date. The technical pitfalls of the CRISPR/Cas9 and the comparative approaches in evaluating this technique with respect to other available alternatives are also described briefly. Furthermore, the review also discussed the clinical aspects and the ethical, legal, and social issues associated with the use of CRISPR/Cas9.

Kaposi's sarcoma herpesvirus (KSHV) microRNA K12-1 functions as an oncogene by activating NF-κB/IL-6/STAT3 signaling.

The human oncogenic virus Kaposi's sarcoma herpesvirus (KSHV) is the most common cause of malignancies among AIDS patients. KSHV possesses over hundred genes, including 25 microRNAs (miRNAs). The roles of these miRNAs and many other viral genes in KSHV biology and pathogenesis remain largely unknown. Accordingly, the molecular mechanisms by which KSHV induces tumorigenesis are still poorly defined. Here, we identify KSHV miRNA K12-1 (miR-K12-1) as a novel viral oncogene by activating two important transcription factors, nuclear factor-κb (NF-κB) and signal transducer and activator of transcription 3 (STAT3). Interestingly, miR-K12-1 activates STAT3 indirectly through inducing NF-κB activation and NF-κB-dependent expression of the cytokine interleukin-6 (IL-6) by repressing the expression of the NF-κB inhibitor IκBα. Accordingly, expression of ectopic IκBα or knockdown of NF-κB RelA, IL-6 or STAT3 prevents expression of cell growth genes and suppresses the oncogenicities of both miR-K12-1 and KSHV. These data identify miR-K12-1/NF-κB/IL-6/STAT3 as a novel oncogenic signaling underlying KSHV tumorigenesis. These data also provide the first evidence showing that IL-6/STAT3 signaling acts as an essential mediator of NF-κB oncogenic actions. These findings significantly improve our understanding of KSHV pathogenesis and oncogenic interaction between NF-κB and STAT3.

T-cell Primary Effusion Lymphoma in an Elderly HIV-Negative Patient Coinfected With Human Kaposi Sarcoma Virus and Epstein-Barr Virus

Primary effusion lymphoma (PEL), one of a few neoplasms associated with human Kaposi sarcoma virus (HKSV), also known as human herpesvirus 8 (HHV8), is typically a B-cell lymphoma occurring in HIV-positive patients. Herein we report an unusual PEL of T-cell origin in an 80-year-old immunocompetent HIV-negative man in which the lymphoma cells were positive for both HHV8 and Epstein-Barr virus …

Polymerase chain reaction for detection of Kaposi's sarcoma virus in breast tumors

Human Herpes Virus 8 (HHV8) causes Kaposi’s sarcoma, a common cancer among AIDS patients. It is proposed that this virus plays a role in formation of some blood vessel and lymphoma tumors. This study aimed to investigate the frequency of KSHV among benign and malignant breast tumors. A total of 24 carcinomas and 24 fibroadenomas paraffin embedded tumoral tissue samples were obtained from the pathology sections of Toos and Firoozgar hospitals in Tehran, Iran. All samples had been collected from patients during a period of time effective from June 2013 to February 2014. DNA was extracted from all samples and their infection with HHV8 was examined by PCR technique. The results obtained by this study showed that 6 out of 24 carcinoma samples (25%) were infected by KSHV, while the number of fibroadenoma samples infected by this virus was 9 (37.5%). The frequency of HHV8 infection was different among malignant and benign tumors. Based on the results obtained by this study, KSHV was observed in both benign and malignant tumors. Since KSHV was observed in both types of tumors therefore, it may not have significant relationship with tumor type. The role of KSHV in vessel tumors has been proved by many studies during the past decade. Some other studies have also defined a role for this virus in formation of breast fibroadenoma tumor. Therefore, further studies are needed to define the influence of this virus in breast tumors formation.

A Rare Case of Multicentric Extracavitary Solid Primary Effusion Lymphoma (ECPEL) Diagnosed by Upper Endoscopy and Colonoscopy

Purpose: A 52-year-old male with HIV/AIDS on HAART (non-compliant) was admitted for hypotension, anemia, weight loss and malaise. Laboratory findings: CD4 cells 3% (30% to 61%); CD8+cells 78% (12% to 42%); CD4:CD8 ratio 0.04 (0.86 to 5.0); white blood cell count 9.7 (4.8 to 10.8); hemoglobin 3.4 g (11.0 to 15.6 g). Total bilirubin 6.4 mg (0.2 to 1.2 mg/dl), direct bilirubin 4.9 (0.0 to 0.5 mg/dl), lactate dehydrogenase 960 (125 to 243 U/L). Imaging Studies: CT scan of chest, abdomen and pelvis showed several regions of soft tissue prominence in the pancreatic head, upper retro peritoneum and ascending colon. Bone marrow biopsy: Large granular lymphocytes that could be reactive or neoplastic. Immunohistochemistry showed MUM1 (multiple myeloma oncogene 1) positive and negative for CD20, CD3, CD30, CD15, CD79a, PAX-5, carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9). EGD and colonoscopy were performed for anemia and abnormal findings on CT scan. EGD showed 3 friable nodules, the largest measuring 2x3 cm in the body of the stomach. The nodules bled on contact and were biopsied (Figure 1). Colonoscopy showed a large friable mass seen in the transverse colon and was biopsied. Histopathology of gastric nodules and colonic mass were consistent with solid Primary Effusion Lymphoma. The neoplastic cells were positive for Epstein Barr (EBV) and Kaposi's Sarcoma Virus (KSHV/HHV8). PEL is seen in body cavities such as the pleural space, pericardium and peritoneum. Extracavitary Solid Primary Effusion Lymphoma (ECPEL) is a rare occurrence and is often associated with Kaposi's sarcoma or multicentric Castleman's disease. It is seen in less than 1% of HIV/AIDS related lymphomas and is also reported rarely after solid organ transplantation. Detection of HHV8 in the neoplastic cells is the only confirmatory diagnostic test in PEL and ECPEL. This case represents an even rarer condition with ECPEL, involving multiple sites, and readily diagnosed by upper endoscopy and colonoscopy.Figure: [1338] Nodule in the body of stomach.

Conservation of a Triple-Helix-Forming RNA Stability Element in Noncoding and Genomic RNAs of Diverse Viruses

Abundant expression of the long noncoding (lnc) PAN (polyadenylated nuclear) RNA by the human oncogenic gammaherpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) depends on a cis-element called the expression and nuclear retention element (ENE). The ENE upregulates PAN RNA by inhibiting its rapid nuclear decay through triple-helix formation with the poly(A) tail. Using structure-based bioinformatics, we identified six ENE-like elements in evolutionarily diverse viral genomes. Five are in double-stranded DNA viruses, including mammalian herpesviruses, insect polydnaviruses, and a protist mimivirus. One is in an insect picorna-like positive-strand RNA virus, suggesting that the ENE can counteract cytoplasmic as well as nuclear RNA decay pathways. Functionality of four of the ENEs was demonstrated by increased accumulation of an intronless polyadenylated reporter transcript in human cells. Identification of these ENEs enabled the discovery of PAN RNA homologs in two additional gammaherpesviruses, RRV and EHV2. Our findings demonstrate that searching for structural elements can lead to rapid identification of lncRNAs.

Abstract LB-68: Mouse mammary tumor virus suppress apoptosis through Src signaling in the mammary epithelial cells

Abstract Many receptors in the hematopoietic immune cells use common signaling pathway that relies on immunoreceptor tyrosine-based activation motif (ITAM). ITAMs are highly conserved sequence. Signal transduction by these motifs is mediated by Src family tyrosine kinases including Lyn, Fyn, Lck. ITAM bearing proteins are found in many oncogenic viruses and associated with transformation and tumorigenesis in epithelial and endothelial cells. These proteins include Epstein Barr Virus LMP2A, Kaposi's sarcoma virus K1, and bovine leukemia virus gp30. MMTV envelope protein is another viral ITAM bearing protein implicated in mammary tumor development. We previously have shown that MMTV envelope protein expression transform mouse mammary epithelial cells and Src kinases are important mediators in this transformation. To study how ITAM signaling affects transformation and progression of mammary tumor we developed mammary cell lines that express MMTV provirus and have a mutated ITAM counterpart. Using PCR based expression profiling we found that MMTV-ITAM turns on the embryonic transcription factors and induce epithelial-mesenchymal transition which is important in malignant tumor progression. Many genes related to cell adhesion and invasion was changed. Anti-apoptotic regulator bcl-2 level was significantly increased. Importantly MMTV expressing cells became resistant to apoptosis induced by serum starvation. Cells transduced with ITAM mutated MMTV were indistinguishable from wild type cells. We also found Src kinase, a downstream signal transducer of ITAM signaling is activated in the MMTV expressing cells, and MMTV induced apoptosis resistance was completely restored by Src inhibitor PP2. Our results show that MMTV suppress apoptosis through ITAM mediated Src tyrosin kinase signaling. The studies in signaling pathways and apoptosis resistance induced by ITAM containing proteins in nonhematopoietic cells could lead to the development of effective treatment of cancers in which ITAM-mediated signaling plays a role. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-68. doi:1538-7445.AM2012-LB-68

Signal transducer and activator of transcription 3 (STAT3) and survivin induction by varicella-zoster virus promote replication and skin pathogenesis

Varicella-zoster virus (VZV) is a human α-herpesvirus that causes varicella (chickenpox) during primary infection and zoster (shingles) upon reactivation. Like other viruses, VZV must subvert the intrinsic antiviral defenses of differentiated human cells to produce progeny virions. Accordingly, VZV inhibits the activation of the cellular transcription factors IFN regulatory factor 3 (IRF3) and signal transducers and activators of transcription 1 (STAT1), thereby downregulating antiviral factors, including IFNs. Conversely, in this study, we found that VZV triggers STAT3 phosphorylation in cells infected in vitro and in human skin xenografts in SCID mice in vivo and that STAT3 activation induces the anti-apoptotic protein survivin. Small-molecule inhibitors of STAT3 phosphorylation and survivin restrict VZV replication in vitro, and VZV infection of skin xenografts in vivo is markedly impaired by the administration of the phospho-STAT3 inhibitor S3I-201. STAT3 and survivin are required for malignant transformation caused by γ-herpesviruses, such as Kaposi's sarcoma virus. We show that STAT3 activation is also critical for VZV, a nononcogenic herpesvirus, via a survivin-dependent mechanism. Furthermore, STAT3 activation is critical for the life cycle of the virus because VZV skin infection is necessary for viral transmission and persistence in the human population. Therefore, we conclude that takeover of this major cell-signaling pathway is necessary, independent of cell transformation, for herpesvirus pathogenesis and that STAT3 activation and up-regulation of survivin is a common mechanism important for the pathogenesis of lytic as well as tumorigenic herpesviruses.

Epstein-Barr Virus Hijacks Cell-Cycle Machinery

The viruses associated with human cancer include Epstein Barr virus (EBV), human papilloma virus (HPV), human T-cell lymphotrophic virus (HTVL-1), Kaposi sarcoma virus (KSHV), hepatitis C virus (HCV), and hepatitis B virus (HBV). Our understanding of how these viruses operate has come a long way since Epstein Barr virus, the first human tumor virus, was identified from the cells of a patient with Burkitt's lymphoma in 1964. Those studies provide a framework for understanding how EBV perturbs cellular pathways, contributing to the development of cancer.

Herpesviridae and novel inhibitors

Herpesviridae comprises a large family of double-stranded DNA viruses that infect both animals and humans. Eight herpesviruses are known to infect humans: herpes simplex virus type-1 and -2, varicella zoster virus, human cytomegalovirus, Epstein-Barr virus, human herpesvirus 6 type-A and -B, human herpesvirus type-7 and -8 or Kaposi's sarcoma virus. Despite the fact that the past two decades have been evolutionary in the development of antiviral agents, therapeutic choices are restricted by limited efficacy and toxicity. Viral infections remain the cause of significant mortality worldwide, thus indicating the high medical need for the introduction of novel promising compounds in the antiviral chemotherapy era. This review focuses on recent data regarding several novel groups of agents that have proved to be effective as antiherpetic drugs. The agents mentioned are those considered to be the most likely candidates for entering clinical trials and those in the process of being granted approval by the US Food and Drug Administration. The diversity in their molecular mechanism of action highlights the different perspectives currently encountered in the era of antiviral therapy.

Molecular Interaction between a Bcl_2 Homolog from Kaposi Sarcoma Virus and p53

Comparison of domain structure and sequence between KSHV Bcl-2 and human Bcl-2 family proteins (A) Human Bcl-2 family proteins are classified into three subfamilies (Bcl-2, Bax, an d BH3-only). Bcl-2 homology (BH) domains and transmembrane segment (TM) are indicated. (B) Sequence alignment between KSHV Bcl-2 and human Bcl-2. The BH domains and TM are shown below the sequence.