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Kaposi's sarcoma-associated herpesvirus infection and Kaposi's sarcoma in Brazil
Ramos-da-Silva, S.;Elgui-de-Oliveira, D.;Borges, L.;Bacchi, C.E.;
Brazilian Journal of Medical and Biological Research , 2006, DOI: 10.1590/S0100-879X2006000500002
Abstract: kaposi's sarcoma (ks) became a critical health issue with the emergence of acquired immunodeficiency syndrome (aids) in the 1980s. four clinical-epidemiological forms of ks have been described: classical ks, endemic ks, iatrogenic ks, and aids-associated ks. in 1994, kaposi's sarcoma-associated herpesvirus (kshv) or human herpesvirus type 8 was identified by chang and colleagues, and has been detected worldwide at frequencies ranging from 80 to 100%. the aim of the present study was to evaluate the frequency of kshv infection in ks lesions from hiv-positive and hiv-negative patients in brazil, as well as to review the current knowledge about ks transmission and detection. for these purposes, dna from 51 cases of ks was assessed by pcr: 20 (39.2%) cases of classical ks, 29 (56.9%) of aids-associated ks and 2 (3.9%) of iatrogenic ks. most patients were males (7.5:1, m/f), and mean age was 47.9 years (sd = ± 18.7 years). as expected, hiv-positive ks patients were younger than patients with classical ks. on the other hand, patients with aids-associated ks have early lesions (patch and plaque) compared to classical ks patients (predominantly nodular lesions). this is assumed to be the result of the early diagnose of ks in the hiv-positive setting. kshv infection was detected by pcr in almost all cases (48/51; 94.1%), irrespectively of the clinical-epidemiological form of ks. these results show that kshv is associated with all forms of ks in brazilian patients, a fact that supports the role of this virus in ks pathogenesis.
Kaposi's sarcoma-associated herpesvirus infection and Kaposi's sarcoma in Brazil  [cached]
Ramos-da-Silva S.,Elgui-de-Oliveira D.,Borges L.,Bacchi C.E.
Brazilian Journal of Medical and Biological Research , 2006,
Abstract: Kaposi's sarcoma (KS) became a critical health issue with the emergence of acquired immunodeficiency syndrome (AIDS) in the 1980s. Four clinical-epidemiological forms of KS have been described: classical KS, endemic KS, iatrogenic KS, and AIDS-associated KS. In 1994, Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus type 8 was identified by Chang and colleagues, and has been detected worldwide at frequencies ranging from 80 to 100%. The aim of the present study was to evaluate the frequency of KSHV infection in KS lesions from HIV-positive and HIV-negative patients in Brazil, as well as to review the current knowledge about KS transmission and detection. For these purposes, DNA from 51 cases of KS was assessed by PCR: 20 (39.2%) cases of classical KS, 29 (56.9%) of AIDS-associated KS and 2 (3.9%) of iatrogenic KS. Most patients were males (7.5:1, M/F), and mean age was 47.9 years (SD = ± 18.7 years). As expected, HIV-positive KS patients were younger than patients with classical KS. On the other hand, patients with AIDS-associated KS have early lesions (patch and plaque) compared to classical KS patients (predominantly nodular lesions). This is assumed to be the result of the early diagnose of KS in the HIV-positive setting. KSHV infection was detected by PCR in almost all cases (48/51; 94.1%), irrespectively of the clinical-epidemiological form of KS. These results show that KSHV is associated with all forms of KS in Brazilian patients, a fact that supports the role of this virus in KS pathogenesis.
Non-Human Primate Model of Kaposi's Sarcoma-Associated Herpesvirus Infection  [PDF]
Heesoon Chang,Lynn M. Wachtman,Christine B. Pearson,Jong-Soo Lee,Hye-Ra Lee,Steven H. Lee,Jeffrey Vieira,Keith G. Mansfield,Jae U. Jung
PLOS Pathogens , 2009, DOI: 10.1371/journal.ppat.1000606
Abstract: Since Kaposi's sarcoma-associated herpesvirus (KSHV or human herpesvirus 8) was first identified in Kaposi's sarcoma (KS) lesions of HIV-infected individuals with AIDS, the basic biological understanding of KSHV has progressed remarkably. However, the absence of a proper animal model for KSHV continues to impede direct in vivo studies of viral replication, persistence, and pathogenesis. In response to this need for an animal model of KSHV infection, we have explored whether common marmosets can be experimentally infected with human KSHV. Here, we report the successful zoonotic transmission of KSHV into common marmosets (Callithrix jacchus, Cj), a New World primate. Marmosets infected with recombinant KSHV rapidly seroconverted and maintained a vigorous anti-KSHV antibody response. KSHV DNA and latent nuclear antigen (LANA) were readily detected in the peripheral blood mononuclear cells (PBMCs) and various tissues of infected marmosets. Remarkably, one orally infected marmoset developed a KS-like skin lesion with the characteristic infiltration of leukocytes by spindle cells positive for KSHV DNA and proteins. These results demonstrate that human KSHV infects common marmosets, establishes an efficient persistent infection, and occasionally leads to a KS-like skin lesion. This is the first animal model to significantly elaborate the important aspects of KSHV infection in humans and will aid in the future design of vaccines against KSHV and anti-viral therapies targeting KSHV coinfected tumor cells.
Exploitation of the Complement System by Oncogenic Kaposi's Sarcoma-Associated Herpesvirus for Cell Survival and Persistent Infection  [PDF]
Myung-Shin Lee,Tiffany Jones,Dae-Yong Song,Jae-Hyuk Jang,Jae U. Jung,Shou-Jiang Gao
PLOS Pathogens , 2014, DOI: doi/10.1371/journal.ppat.1004412
Abstract: During evolution, herpesviruses have developed numerous, and often very ingenious, strategies to counteract efficient host immunity. Specifically, Kaposi's sarcoma-associated herpesvirus (KSHV) eludes host immunity by undergoing a dormant stage, called latency wherein it expresses a minimal number of viral proteins to evade host immune activation. Here, we show that during latency, KSHV hijacks the complement pathway to promote cell survival. We detected strong deposition of complement membrane attack complex C5b-9 and the complement component C3 activated product C3b on Kaposi's sarcoma spindle tumor cells, and on human endothelial cells latently infected by KSHV, TIME-KSHV and TIVE-LTC, but not on their respective uninfected control cells, TIME and TIVE. We further showed that complement activation in latently KSHV-infected cells was mediated by the alternative complement pathway through down-regulation of cell surface complement regulatory proteins CD55 and CD59. Interestingly, complement activation caused minimal cell death but promoted the survival of latently KSHV-infected cells grown in medium depleted of growth factors. We found that complement activation increased STAT3 tyrosine phosphorylation (Y705) of KSHV-infected cells, which was required for the enhanced cell survival. Furthermore, overexpression of either CD55 or CD59 in latently KSHV-infected cells was sufficient to inhibit complement activation, prevent STAT3 Y705 phosphorylation and abolish the enhanced survival of cells cultured in growth factor-depleted condition. Together, these results demonstrate a novel mechanism by which an oncogenic virus subverts and exploits the host innate immune system to promote viral persistent infection.
Seroprevalence and risk factors of Kaposi's sarcoma-associated herpesvirus infection among the general Uygur population from south and north region of Xinjiang, China
Hui Wang, Jian Liu, Dilimulati, Liang Li, Zhihui Ren, Hao Wen, Xing Wang
Virology Journal , 2011, DOI: 10.1186/1743-422x-8-539
Abstract: Seroprevalence of KSHV in South and North Xinjiang was 23.1% and 25.9%, respectively. Older age was independently associated with higher KSHV seroprevalence. In subjects from South Xinjiang, lower educational level and reported drinking were each independently associated with higher KSHV seroprevalence. Furthermore, the antibody titer was significantly lower in both south and north KSHV seropositive individuals compared with KS patients, as analyzed by gradient dilution (P < 0.001).KSHV is highly prevalent in the general Uygur population in both South and North Xinjiang. Interestingly, the infection rate of KSHV in these two geographical areas did not correlate well with KS incidence. Perhaps unknown factors exist that promote the progression of KSHV infection to KS development in the local minority groups.Kaposi sarcoma (KS) is a mesenchymal tumour involving blood and lymphatic vessels [1]. KS can be classified according to its clinical and epidemiological characteristics and the different types include: classical, acquired immunodeficiency syndrome (AIDS)-related, iatrogenic and endemic KS [2,3]. Notably, KS is the most common cancer associated with AIDS worldwide [4]. Approximately 20% of AIDS patients develop KS in Western countries and AIDS-KS is the major cause of death for about 50% of AIDS patients [5,6]. Kaposi's sarcoma-associated herpesvirus (KSHV) also known as Human herpesvirus 8 (HHV-8 ), is an oncogenic virus with a causal role in the development of KS [2,7-9], and two other AIDS-related lymphoproliferative disorders: primary effusion lymphoma (PEL) and the plasma-cell variant of multicentric Castleman's disease (MCD) [10]. KSHV has been detected in the lesions of nearly all patients with KS [11,12], and when detected in blood it is predictive of the development of KS [8,13].KSHV prevalence exhibits considerable variation in different geographical regions and populations. Several studies have demonstrated that KSHV seroprevalence correlates with the o
Parasite infection is associated with Kaposi's sarcoma associated herpesvirus (KSHV) in Ugandan women
Katie Wakeham, Emily L Webb, Ismail Sebina, Lawrence Muhangi, Wendell Miley, W Thomas Johnson, Juliet Ndibazza, Alison M Elliott, Denise Whitby, Robert Newton
Infectious Agents and Cancer , 2011, DOI: 10.1186/1750-9378-6-15
Abstract: Seroprevalence of KSHV was higher in women with malaria parasitaemia (73% vs 60% p = 0.01), hookworm (67% vs 56% p = 0.001) and Mansonella perstans (69% vs 59% p = 0.05); seroprevalence increased with increasing intensity of hookworm infection (p < 0.001[trend]). No associations were found for HIV, five other parasites or active syphilis. These effects were not explained by socioeconomic status or education.Specific parasite infections are associated with presence of antibodies against KSHV, perhaps mediated via their effect on immune function.Infection with KSHV is the underlying cause of Kaposi's sarcoma (KS), although it may not be sufficient [1]. Immune suppression, such as that caused by human immunodeficiency virus (HIV), significantly increases the risk of KS among KSHV infected people and is associated with increased viral load and viral shedding [2-8]. Among people without HIV infection or other forms of overt immune suppression, geographic and temporal variation in the incidence of KS and in the prevalence of KSHV suggest that cofactors may be important in facilitating both transmission and disease [9-18]. Whether cofactors act directly or via effects on the immune system is unclear [19].Many environmental co-factors for KSHV transmission and disease have been suggested, including volcanic soils [20], limestone [21] and 'oncoweeds' - that is plants with carcinogenic properties or the ability to reactivate KSHV in vitro - although epidemiologic evidence of a role for these agents remains scant [22]. Ecological studies in the Mediterranean area found that eradication of mosquitoes and other blood sucking arthropods was associated with declines both in the prevalence of KSHV and in the incidence of KS [9-14,18,23]. The 'promoter arthropod hypothesis' suggests that insect blood feeding increases KSHV transmission through viral reactivation and KS through inflammatory mechanisms associated with the bite [11,14].Studies of KS in Africa have identified risk facto
Glutamate Secretion and Metabotropic Glutamate Receptor 1 Expression during Kaposi's Sarcoma-Associated Herpesvirus Infection Promotes Cell Proliferation  [PDF]
Mohanan Valiya Veettil ,Dipanjan Dutta,Virginie Bottero,Chirosree Bandyopadhyay,Olsi Gjyshi,Neelam Sharma-Walia,Sujoy Dutta,Bala Chandran
PLOS Pathogens , 2014, DOI: doi/10.1371/journal.ppat.1004389
Abstract: Kaposi's sarcoma associated herpesvirus (KSHV) is etiologically associated with endothelial Kaposi's sarcoma (KS) and B-cell proliferative primary effusion lymphoma (PEL), common malignancies seen in immunocompromised HIV-1 infected patients. The progression of these cancers occurs by the proliferation of cells latently infected with KSHV, which is highly dependent on autocrine and paracrine factors secreted from the infected cells. Glutamate and glutamate receptors have emerged as key regulators of intracellular signaling pathways and cell proliferation. However, whether they play any role in the pathological changes associated with virus induced oncogenesis is not known. Here, we report the first systematic study of the role of glutamate and its metabotropic glutamate receptor 1 (mGluR1) in KSHV infected cell proliferation. Our studies show increased glutamate secretion and glutaminase expression during de novo KSHV infection of endothelial cells as well as in KSHV latently infected endothelial and B-cells. Increased mGluR1 expression was detected in KSHV infected KS and PEL tissue sections. Increased c-Myc and glutaminase expression in the infected cells was mediated by KSHV latency associated nuclear antigen 1 (LANA-1). In addition, mGluR1 expression regulating host RE-1 silencing transcription factor/neuron restrictive silencer factor (REST/NRSF) was retained in the cytoplasm of infected cells. KSHV latent protein Kaposin A was also involved in the over expression of mGluR1 by interacting with REST in the cytoplasm of infected cells and by regulating the phosphorylation of REST and interaction with β-TRCP for ubiquitination. Colocalization of Kaposin A with REST was also observed in KS and PEL tissue samples. KSHV infected cell proliferation was significantly inhibited by glutamate release inhibitor and mGluR1 antagonists. These studies demonstrated that elevated glutamate secretion and mGluR1 expression play a role in KSHV induced cell proliferation and suggest that targeting glutamate and mGluR1 is an attractive therapeutic strategy to effectively control the KSHV associated malignancies.
Kaposi's Sarcoma-Associated Herpesvirus Induces Nrf2 during De Novo Infection of Endothelial Cells to Create a Microenvironment Conducive to Infection  [PDF]
Olsi Gjyshi,Virginie Bottero,Mohanan Valliya Veettil,Sujoy Dutta,Vivek Vikram Singh,Leela Chikoti,Bala Chandran
PLOS Pathogens , 2014, DOI: doi/10.1371/journal.ppat.1004460
Abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS) and primary effusion B-cell lymphoma. KSHV induces reactive oxygen species (ROS) early during infection of human dermal microvascular endothelial (HMVEC-d) cells that are critical for virus entry. One of the downstream targets of ROS is nuclear factor E2-related factor 2 (Nrf2), a transcription factor with important anti-oxidative functions. Here, we show that KS skin lesions have high Nrf2 activity compared to healthy skin tissue. Within 30 minutes of de novo KSHV infection of HMVEC-d cells, we observed Nrf2 activation through ROS-mediated dissociation from its inhibitor Keap1, Ser-40 phosphorylation, and subsequent nuclear translocation. KSHV binding and consequent signaling through Src, PI3-K and PKC-ζ were also important for Nrf2 stability, phosphorylation and transcriptional activity. Although Nrf2 was dispensable for ROS homeostasis, it was essential for the induction of COX-2, VEGF-A, VEGF-D, Bcl-2, NQO1, GCS, HO1, TKT, TALDO and G6PD gene expression in KSHV-infected HMVEC-d cells. The COX-2 product PGE2 induced Nrf2 activity through paracrine and autocrine signaling, creating a feed-forward loop between COX-2 and Nrf2. vFLIP, a product of KSHV latent gene ORF71, induced Nrf2 and its target genes NQO1 and HO1. Activated Nrf2 colocalized with the KSHV genome as well as with the latency protein LANA-1. Nrf2 knockdown enhanced ORF73 expression while reducing ORF50 and other lytic gene expression without affecting KSHV entry or genome nuclear delivery. Collectively, these studies for the first time demonstrate that during de novo infection, KSHV induces Nrf2 through intricate mechanisms involving multiple signal molecules, which is important for its ability to manipulate host and viral genes, creating a microenvironment conducive to KSHV infection. Thus, Nrf2 is a potential attractive target to intervene in KSHV infection and the associated maladies.
Human Herpesvirus-8 Infection Associated with Kaposi Sarcoma, Multicentric Castleman's Disease, and Plasmablastic Microlymphoma in a Man with AIDS: A Case Report with Review of Pathophysiologic Processes  [PDF]
Christian Eaton,Russell Dorer,David M. Aboulafia
Pathology Research International , 2011, DOI: 10.4061/2011/647518
Abstract: Kaposi sarcoma (KS), multicentric Castleman's disease (MCD), and plasmablastic microlymphoma, are all linked to human herpesvirus-8 (HHV-8) infection and HIV-induced immunodeficiency. Herein, we describe the case of a Kenyan man diagnosed with HIV in 2000. He deferred highly active antiretroviral therapy (HAART) and remained in good health until his CD4+ count declined in 2006. He was hospitalized with bacterial pneumonia in 2008, after which he agreed to take HAART but did so sporadically. In 2010, he was hospitalized with fever, lymphadenopathy, pancytopenia, and an elevated HHV-8 viral load. A lymph node biopsy showed findings consistent with KS, MCD, and plasmablastic microlymphoma. Eight months after starting liposomal doxorubicin, Rituximab, and a new HAART regimen, he has improved clinically, and his HIV and HHV-8 viral loads are suppressed. These three conditions, found in the same lymph node, underscore the inflammatory and malignant potential of HHV-8, particularly in the milieu of HIV-induced immunodeficiency. 1. Introduction In the current era of highly active antiretroviral therapy (HAART), people infected with HIV are not only less likely to develop AIDS-defining infections, they are also less likely to be diagnosed with an AIDS-defining neoplasm (i.e., Kaposi Sarcoma (KS) or non-Hodgkins lymphoma (NHL)) [1–3]. As these individuals live to their sixth decade of life and beyond, cancers associated with lifestyle choices and aging (i.e., lung, liver, and anal carcinomas) are increasingly important barriers to survival [4–6]. However, AIDS-defining malignancies remain a significant cause of morbidity and mortality for those individuals who are not on HAART because they are unaware of their HIV serostatus, they do not have access to HAART, or they are poorly adherent with prescribed therapies [7]. KS is etiologically linked to human herpesvirus-8 (HHV-8), also known as KS-associated herpesvirus (KSHV) [8]. The HHV-8 genome contains numerous genes that code for proteins with recognizable homology to human proteins, including an interleukin-6 (IL-6) homologue [9]. IL-6 has multiple systemic effects including the support of hematopoiesis and stimulation of B lymphocyte and plasma cell growth. When expressed in physiologic excess, IL-6 may contribute to dysregulation of immune responses [10]. IL-6 is also a major mediator of the systemic symptoms associated with Castleman's disease (CD) [11, 12]. CD is a heterogeneous group of lymphoproliferative disorders of unknown etiology. Unlike unicentric CD, multicentric CD (MCD) is strongly associated with
The Chromatin Landscape of Kaposi’s Sarcoma-Associated Herpesvirus  [PDF]
Zsolt Toth,Kevin Brulois,Jae U. Jung
Viruses , 2013, DOI: 10.3390/v5051346
Abstract: Kaposi’s sarcoma-associated herpesvirus is an oncogenic γ-herpesvirus that causes latent infection in humans. In cells, the viral genome adopts a highly organized chromatin structure, which is controlled by a wide variety of cellular and viral chromatin regulatory factors. In the past few years, interrogation of the chromatinized KSHV genome by whole genome-analyzing tools revealed that the complex chromatin landscape spanning the viral genome in infected cells has important regulatory roles during the viral life cycle. This review summarizes the most recent findings regarding the role of histone modifications, histone modifying enzymes, DNA methylation, microRNAs, non-coding RNAs and the nuclear organization of the KSHV epigenome in the regulation of latent and lytic viral gene expression programs as well as their connection to KSHV-associated pathogenesis.
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