ABSTRACT
A 68-year-old Latino man presented at our clinic with asymptomatic, indurated red nodules and macules of 2-month duration on the left arm, forearm, and palm (Figure 1). Performed punch biopsy presented characteristic -features of Kaposi sarcoma (KS). Immunohistochemistry was positive for human herpesvirus 8 (HHV8), a highly correlated viral marker, confirming the diagnosis of KS (Figure 2). He was referred to oncology for further management, where he was found to be fully immunocompetent with a negative assessment of human immunodefi-ciency virus (HIV). Computed tomography (CT) performed of his chest and abdomen revealed no involvement of internal organs.
Subject(s)
Immunocompetence , Sarcoma, Kaposi , Humans , Male , Aged , Sarcoma, Kaposi/diagnosis , Sarcoma, Kaposi/pathology , Herpesvirus 8, Human/isolation & purification , Skin Neoplasms/diagnosis , Skin Neoplasms/pathologyABSTRACT
Kaposi sarcoma (KS) is a neoplasm of vascular origin that promotes angiogenesis and the growth of endothelial cells triggered by the Kaposi Sarcoma-associated Herpes Virus (KSHV). When associated with HIV, KSHV becomes more aggressive and rapidly evolves. The HIV-1 TAT protein can be essential in developing AIDS-associated KS by promoting angiogenesis and increasing KSHV replication. Therefore, we evaluated the genetic profile of the first exon of tat gene among groups of people living with HIV (PLHIV) with (case group, n = 36) or without KS, this later with (positive control group, n = 46) and without KSHV infection (negative control group, n = 24); all individuals under antiretroviral therapy. The genetic diversity, the DN/DS ratio, and the genetic entropy of the first exon of tat were higher in the case group, followed by the positive control group, which was higher than the negative control group. The number of tat codons under positive selection was seven in the case group, six in the positive control group, and one in the negative control group. The prevalence of HIV viral loads below the detection limit was equal in the case and positive control groups, which were lower than in the negative control group. The mean CD4+ T cell counts were higher in the negative control group, followed by the positive control group, and followed by the case group. These results emphasize the negative influence of KSHV in antiretroviral treatment, as well as the HIV-specific TAT profile among PLHIV who developed KS.
Subject(s)
Coinfection , HIV Infections , Herpesvirus 8, Human , Sarcoma, Kaposi , tat Gene Products, Human Immunodeficiency Virus , Humans , Sarcoma, Kaposi/virology , HIV Infections/complications , HIV Infections/drug therapy , HIV Infections/virology , Male , Herpesvirus 8, Human/genetics , Female , Adult , Middle Aged , tat Gene Products, Human Immunodeficiency Virus/genetics , Coinfection/virology , Coinfection/drug therapy , HIV-1/genetics , HIV-1/drug effects , Genetic Variation , Viral Load , Anti-Retroviral Agents/therapeutic use , CD4 Lymphocyte CountABSTRACT
Kaposi's sarcoma (KS) is an angio-proliferative disease with a viral etiology and a multifactorial pathogenesis that results from immune dysfunction. In patients affected by latent viral infections such as herpesviruses, SARS-CoV-2 infection may result in lytic cycle reactivation in host cells. A robust immune system response is crucial for eliminating pathogens and resolving both latent and non-latent viral infections. We report a case series of KS characterized by tumor progression after SARS-CoV-2 infection. We performed a systematic literature review of the PubMed/MEDLINE and EMBASE databases. The keyword terms included "SARS-CoV-2," "HHV-8," "Kaposi's sarcoma," "IL-6," and "COVID-19." English language restriction was applied. Items not covered by our study were excluded. KS is a complex disease linked to an impaired immune system. Conditions that result in temporary or permanent immunodeficiency can trigger viral reactivation or exacerbate an existing disease. It is feasible that the increase in cytokine levels in COVID-19 patients, coupled with lymphocyte downregulation and treatment that induces herpesvirus lytic reactivation, may contribute to the progression of KS after SARS-CoV-2 infection. These observations suggest that patients with KS should be clinically monitored both during and after SARS-CoV-2 infection. Nevertheless, prospective data should be collected to validate this hypothesis and enhance our understanding of the mechanisms implicated in the onset or progression of KS.
Subject(s)
COVID-19 , Herpesvirus 8, Human , SARS-CoV-2 , Sarcoma, Kaposi , Humans , COVID-19/immunology , COVID-19/complications , COVID-19/virology , Sarcoma, Kaposi/virology , Male , Middle Aged , Female , Aged , Virus ActivationABSTRACT
Human herpesviruses (HHVs) cause a wide variety of central nervous system (CNS) infections including meningitis and encephalitis. While HHV-8 is not typically associated with neurological diseases, several studies have indicated a relationship, such as secondary central nervous system (CNS) metastases and a few isolated cases of HHV-8 encephalitis in acquired immunodeficiency syndrome (HIV). However, it has not been previously linked to encephalitis in solid organ transplantation (SOT). This case presents the first-ever instance of HHV-8 encephalitis in a SOT recipient. Our case highlights the association of HHV-8-related diseases, such as post-transplant Kaposi's Sarcoma (KS), with encephalitis. The patient was diagnosed with KS before developing neurological symptoms and received a prompt clinical response through intravenous foscarnet and ganciclovir treatment for 14 days. It is important to note that HHV-8 is a rare cause of encephalitis, and diagnosis requires a high index of suspicion in the appropriate clinical context, allowing for the use of antiviral therapy. This case also underscores the importance of considering the possibility of HHV-8-related diseases in SOT recipients, as they are at risk of developing such infections.
Subject(s)
Antiviral Agents , Encephalitis, Viral , Ganciclovir , Herpesviridae Infections , Herpesvirus 8, Human , Sarcoma, Kaposi , Humans , Herpesvirus 8, Human/isolation & purification , Sarcoma, Kaposi/virology , Antiviral Agents/therapeutic use , Male , Herpesviridae Infections/virology , Herpesviridae Infections/complications , Herpesviridae Infections/diagnosis , Encephalitis, Viral/virology , Encephalitis, Viral/diagnosis , Encephalitis, Viral/drug therapy , Ganciclovir/therapeutic use , Foscarnet/therapeutic use , Middle Aged , Transplant Recipients , Organ Transplantation/adverse effectsABSTRACT
Recently published near full-length KSHV genomes from a Cameroon Kaposi sarcoma case-control study showed strong evidence of viral recombination and mixed infections, but no sequence variations associated with disease. Using the same methodology, an additional 102 KSHV genomes from 76 individuals with KSHV-associated diseases have been sequenced. Diagnoses comprise all KSHV-associated diseases (KAD): Kaposi sarcoma (KS), primary effusion lymphoma (PEL), KSHV-associated large cell lymphoma (KSHV-LCL), a type of multicentric Castleman disease (KSHV-MCD), and KSHV inflammatory cytokine syndrome (KICS). Participants originated from 22 different countries, providing the opportunity to obtain new near full-length sequences of a wide diversity of KSHV genomes. These include near full-length sequence of genomes with KSHV K1 subtypes A, B, C, and F as well as subtype E, for which no full sequence was previously available. High levels of recombination were observed. Fourteen individuals (18%) showed evidence of infection with multiple KSHV variants (from two to four unique genomes). Twenty-six comparisons of sequences, obtained from various sampling sites including PBMC, tissue biopsies, oral fluids, and effusions in the same participants, identified near complete genome conservation between different biological compartments. Polymorphisms were identified in coding and non-coding regions, including indels in the K3 and K15 genes and sequence inversions here reported for the first time. One such polymorphism in KSHV ORF46, specific to the KSHV K1 subtype E2, encoded a mutation in the leucine loop extension of the uracil DNA glycosylase that results in alteration of biochemical functions of this protein. This confirms that KSHV sequence variations can have functional consequences warranting further investigation. This study represents the largest and most diverse analysis of KSHV genome sequences to date among individuals with KAD and provides important new information on global KSHV genomics.
Subject(s)
Genome, Viral , Herpesvirus 8, Human , Sarcoma, Kaposi , Humans , Herpesvirus 8, Human/genetics , Sarcoma, Kaposi/virology , Sarcoma, Kaposi/genetics , Male , Female , Middle Aged , Adult , Polymorphism, Genetic , Aged , Herpesviridae Infections/genetics , Herpesviridae Infections/virology , Ethnicity/genetics , Castleman Disease/virology , Castleman Disease/genetics , PhylogenyABSTRACT
Kaposi sarcoma is a rare angioproliferative disease associated with human herpes virus-8 (HHV-8) infection. Kaposi sarcoma is frequent and aggressive in HIV-infected people, whereas the classic form (CKS) generally has an indolent course. Notably, all conventional therapies against Kaposi sarcoma have only temporary efficacy. We have previously shown that indinavir, a HIV protease-inhibitor with direct antiangiogenic and antitumor activity, is safe and effective in patients with early CKS, whereas effects are less prominent in advanced disease, probably due to the larger tumor mass. Therefore, the clinical response to indinavir was assessed in patients with advanced CKS after debulking chemotherapy. This was a monocentric phase 2 trial in elderly with progressive/advanced CKS treated with debulking chemotherapy and indinavir combined, followed by a maintenance phase with indinavir alone. Secondary endpoints included safety and Kaposi sarcoma biomarker evaluation.All evaluable patients (22) responded to debulking therapy. Out of these, 16 entered the indinavir maintenance phase. The overall response rate at end of maintenance was 75% (estimated median response-duration 43 months). Moreover, most responders showed further clinical improvements (lesion number/nodularity) during maintenance and post-treatment follow-up. Notably, after relapse, progressors did not require systemic Kaposi sarcoma therapy and showed clinical improvements (including disease stabilization) remaining on study. Responders also showed immune status amelioration with a consistent B-cell increase and positive changes of other biomarkers, including anti-HHV-8 natural killer activity. In advanced CKS a strategy combining indinavir and chemotherapy is safe and associated with high and durable response rates and it could be rapidly adopted for the clinical management of these patients. SIGNIFICANCE: This phase-2 trial showed that the HIV protease inhibitor indinavir may boost and extend the duration of the effects of chemotherapy in elderly with advanced progressive classic Kaposi sarcoma, without additional toxicity. Further, the amelioration of the immune status seen in responders suggests a better control of HHV-8 infection and tumor-cell killing. Thus, indinavir combined with chemotherapy may represent an important tool for the clinical management of classic Kaposi sarcoma in elderly patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , HIV Protease Inhibitors , Indinavir , Sarcoma, Kaposi , Humans , Sarcoma, Kaposi/drug therapy , Indinavir/therapeutic use , Indinavir/administration & dosage , Indinavir/adverse effects , Male , Female , Aged , HIV Protease Inhibitors/therapeutic use , HIV Protease Inhibitors/administration & dosage , HIV Protease Inhibitors/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Aged, 80 and over , Treatment Outcome , Herpesvirus 8, HumanABSTRACT
Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic herpesvirus that is linked directly to the development of Kaposi's sarcoma. KSHV establishes a latent infection in B cells, which can be reactivated to initiate lytic replication, producing infectious virions. Using pharmacological and genetic silencing approaches, we showed that the voltage-gated K+ channel Kv1.3 in B cells enhanced KSHV lytic replication. The KSHV replication and transcription activator (RTA) protein increased the abundance of Kv1.3 and led to enhanced K+ channel activity and hyperpolarization of the B cell membrane. Enhanced Kv1.3 activity promoted intracellular Ca2+ influx, leading to the Ca2+-driven nuclear localization of KSHV RTA and host nuclear factor of activated T cells (NFAT) proteins and subsequently increased the expression of NFAT1 target genes. KSHV lytic replication and infectious virion production were inhibited by Kv1.3 blockers or silencing. These findings highlight Kv1.3 as a druggable host factor that is key to the successful completion of KSHV lytic replication.
Subject(s)
Herpesvirus 8, Human , Kv1.3 Potassium Channel , NFATC Transcription Factors , Virus Replication , Herpesvirus 8, Human/physiology , Herpesvirus 8, Human/genetics , Herpesvirus 8, Human/metabolism , Humans , Kv1.3 Potassium Channel/metabolism , Kv1.3 Potassium Channel/genetics , Kv1.3 Potassium Channel/antagonists & inhibitors , NFATC Transcription Factors/metabolism , NFATC Transcription Factors/genetics , Immediate-Early Proteins/metabolism , Immediate-Early Proteins/genetics , Trans-Activators/metabolism , Trans-Activators/genetics , B-Lymphocytes/virology , B-Lymphocytes/metabolism , Calcium/metabolism , Sarcoma, Kaposi/virology , Sarcoma, Kaposi/metabolism , Sarcoma, Kaposi/geneticsABSTRACT
Kaposi sarcoma (KS) is a low-grade vascular neoplasm that can be seen in various sites, most commonly seen in skin and mucosal tissues. Cytologic features of KS have been well-documented in the literature, however, since it is rarely seen in visceral organs, it could pose significant diagnostic challenges on fine needle aspiration (FNA) biopsies. We present a case of pulmonary KS diagnosed on transbronchial FNA biopsy in a 70-year-old female bilateral lung allograft recipient 11 months after transplantation. The aspirate smears showed a moderately cellular specimen containing a mixture of small, tightly cohesive clusters and loosely clustered groups of monomorphic, ovoid to spindled cells with moderate nuclear to cytoplasmic ratio. An extensive immunohistochemical panel on the concurrent core biopsy showed the tumor cells to be positive for ERG, KIT, and HHV8, confirming the diagnosis. We compared our case to previously published reports of confirmed pulmonary KS in lung allograft recipients.
Subject(s)
Lung Neoplasms , Lung Transplantation , Sarcoma, Kaposi , Humans , Lung Transplantation/adverse effects , Sarcoma, Kaposi/pathology , Sarcoma, Kaposi/diagnosis , Female , Aged , Lung Neoplasms/pathology , Lung Neoplasms/diagnosis , Biopsy, Fine-Needle , Biopsy, Large-Core NeedleABSTRACT
Kaposi's sarcoma-associated herpesvirus is the etiologic agent of Kaposi's sarcoma and two B-cell malignancies. Recent advancements in sequencing technologies have led to high resolution transcriptomes for several human herpesviruses that densely encode genes on both strands. However, for KSHV progress remained limited due to the overall low percentage of KSHV transcripts, even during lytic replication. To address this challenge, we have developed a target enrichment method to increase the KSHV-specific reads for both short- and long-read sequencing platforms. Furthermore, we combined this approach with the Transcriptome Resolution through Integration of Multi-platform Data (TRIMD) pipeline developed previously to annotate transcript structures. TRIMD first builds a scaffold based on long-read sequencing and validates each transcript feature with supporting evidence from Illumina RNA-Seq and deepCAGE sequencing data. Our stringent innovative approach identified 994 unique KSHV transcripts, thus providing the first high-density KSHV lytic transcriptome. We describe a plethora of novel coding and non-coding KSHV transcript isoforms with alternative untranslated regions, splice junctions and open-reading frames, thus providing deeper insights on gene expression regulation of KSHV. Interestingly, as described for Epstein-Barr virus, we identified transcription start sites that augment long-range transcription and may increase the number of latency-associated genes potentially expressed in KS tumors.
Subject(s)
Alternative Splicing , Herpesvirus 8, Human , Transcriptome , Herpesvirus 8, Human/genetics , Humans , Transcriptome/genetics , Transcription, Genetic , Gene Expression Regulation, Viral , Open Reading Frames/genetics , High-Throughput Nucleotide Sequencing , Sarcoma, Kaposi/virology , Sarcoma, Kaposi/genetics , RNA, Viral/genetics , RNA, Viral/metabolismABSTRACT
Persons with HIV-associated Kaposi's sarcoma (KS) experience three co-existing stigmatizing health conditions: skin disease, HIV, and cancer, which contribute to a complex experience of stigmatization and to delays in diagnosis and treatment. Despite the importance of stigma among these patients, there are few proven stigma-reduction strategies for HIV-associated malignancies. Using qualitative methods, we explore how people with HIV-associated KS in western Kenya between August 2022 and 2023 describe changes in their stigma experience after participation in a multicomponent navigation strategy, which included 1) physical navigation and care coordination, 2) video-based education with motivational survivor stories, 3) travel stipend, 4) health insurance enrollment assistance, 5) health insurance stipend, and 6) peer mentorship. A purposive sample of persons at different stages of chemotherapy treatment were invited to participate. Participants described how a multicomponent navigation strategy contributed to increased knowledge and awareness, a sense of belonging, hope to survive, encouragement, and social support, which served as stigma mitigators, likely counteracting the major drivers of intersectional stigma in HIV-associated KS.
Subject(s)
HIV Infections , Qualitative Research , Sarcoma, Kaposi , Social Stigma , Humans , Sarcoma, Kaposi/psychology , Sarcoma, Kaposi/therapy , Sarcoma, Kaposi/etiology , Sarcoma, Kaposi/epidemiology , HIV Infections/psychology , HIV Infections/complications , Kenya/epidemiology , Male , Female , Adult , Middle Aged , Patient NavigationABSTRACT
Kaposi's sarcoma (KS) is a cancer affecting skin and internal organs for which the Kaposi's sarcoma associated herpesvirus (KSHV) is a necessary cause. Previous work has pursued KS diagnosis by quantifying KSHV DNA in skin biopsies using a point-of-care (POC) device which performs quantitative loop-mediated isothermal amplification (LAMP). These previous studies revealed that extracting DNA from patient biopsies was the rate limiting step in an otherwise rapid process. In this study, a simplified, POC-compatible alkaline DNA extraction, ColdSHOT, was optimized for 0.75 mm human skin punch biopsies. The optimized ColdSHOT extraction consistently produced 40,000+ copies of DNA per 5 µl reaction from 3 mg samples-a yield comparable to standard spin column extractions-within 1 h without significant equipment. The DNA yield was estimated sufficient for KSHV detection from KS-positive patient biopsies, and the LAMP assay was not affected by non-target tissue in the unpurified samples. Furthermore, the yields achieved via ColdSHOT were robust to sample storage in phosphate-buffered saline (PBS) or Tris-EDTA (TE) buffer prior to DNA extraction, and the DNA sample was stable after extraction. The results presented in this study indicate that the ColdSHOT DNA extraction could be implemented to simplify and accelerate the LAMP-based diagnosis of Kaposi's sarcoma using submillimeter biopsy samples.
Subject(s)
DNA, Viral , Herpesvirus 8, Human , Nucleic Acid Amplification Techniques , Sarcoma, Kaposi , Skin , Humans , DNA, Viral/genetics , DNA, Viral/isolation & purification , Herpesvirus 8, Human/isolation & purification , Herpesvirus 8, Human/genetics , Biopsy/methods , Skin/virology , Skin/pathology , Sarcoma, Kaposi/diagnosis , Sarcoma, Kaposi/virology , Sarcoma, Kaposi/pathology , Sarcoma, Kaposi/genetics , Nucleic Acid Amplification Techniques/methods , Point-of-Care Systems , Molecular Diagnostic Techniques/methodsABSTRACT
Kaposiform hemangioendothelioma(KHE) without Kasabach-Merritt phenomenon is a rare tumor primarily observed in pediatric patients; however, its documentation in the literature remains limited. We reported about a 1-year-old boy diagnosed with superficial KHE who received oral propranolol in combination with topical sirolimus and reviewed relevant reports and treatment of superficial KHE.
Subject(s)
Hemangioendothelioma , Propranolol , Sarcoma, Kaposi , Sirolimus , Humans , Infant , Male , Administration, Oral , Biopsy , Hemangioendothelioma/drug therapy , Hemangioendothelioma/diagnosis , Propranolol/administration & dosage , Propranolol/therapeutic use , Sarcoma, Kaposi/drug therapy , Sarcoma, Kaposi/pathology , Sirolimus/administration & dosage , Treatment OutcomeABSTRACT
TRIM32 is often aberrantly expressed in many types of cancers. Kaposi's sarcoma-associated herpesvirus (KSHV) is linked with several human malignancies, including Kaposi's sarcoma and primary effusion lymphomas (PELs). Increasing evidence has demonstrated the crucial role of KSHV lytic replication in viral tumorigenesis. However, the role of TRIM32 in herpesvirus lytic replication remains unclear. Here, we reveal that the expression of TRIM32 is upregulated by KSHV in latency, and reactivation of KSHV lytic replication leads to the inhibition of TRIM32 in PEL cells. Strikingly, RTA, the master regulator of lytic replication, interacts with TRIM32 and dramatically promotes TRIM32 for degradation via the proteasome systems. Inhibition of TRIM32 induces cell apoptosis and in turn inhibits the proliferation and colony formation of KSHV-infected PEL cells and facilitates the reactivation of KSHV lytic replication and virion production. Thus, our data imply that the degradation of TRIM32 is vital for the lytic activation of KSHV and is a potential therapeutic target for KSHV-associated cancers. IMPORTANCE: TRIM32 is associated with many cancers and viral infections; however, the role of TRIM32 in viral oncogenesis remains largely unknown. In this study, we found that the expression of TRIM32 is elevated by Kaposi's sarcoma-associated herpesvirus (KSHV) in latency, and RTA (the master regulator of lytic replication) induces TRIM32 for proteasome degradation upon viral lytic reactivation. This finding provides a potential therapeutic target for KSHV-associated cancers.
Subject(s)
Herpesvirus 8, Human , Immediate-Early Proteins , Proteolysis , Trans-Activators , Transcription Factors , Tripartite Motif Proteins , Ubiquitin-Protein Ligases , Virus Activation , Virus Replication , Humans , Apoptosis , Cell Line , Herpesvirus 8, Human/growth & development , Herpesvirus 8, Human/metabolism , Herpesvirus 8, Human/pathogenicity , Herpesvirus 8, Human/physiology , Immediate-Early Proteins/metabolism , Immediate-Early Proteins/genetics , Lymphoma, Primary Effusion/virology , Lymphoma, Primary Effusion/metabolism , Proteasome Endopeptidase Complex/metabolism , Sarcoma, Kaposi/virology , Sarcoma, Kaposi/metabolism , Trans-Activators/metabolism , Trans-Activators/genetics , Transcription Factors/metabolism , Transcription Factors/genetics , Tripartite Motif Proteins/metabolism , Tripartite Motif Proteins/genetics , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Protein Ligases/genetics , Virus LatencyABSTRACT
Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8, is the causal agent of Kaposi sarcoma, a cancer that appears as tumors on the skin or mucosal surfaces, as well as primary effusion lymphoma and KSHV-associated multicentric Castleman disease, which are B-cell lymphoproliferative disorders. Effective prophylactic and therapeutic strategies against KSHV infection and its associated diseases are needed. To develop these strategies, it is crucial to identify and target viral glycoproteins involved in KSHV infection of host cells. Multiple KSHV glycoproteins expressed on the viral envelope are thought to play a pivotal role in viral infection, but the infection mechanisms involving these glycoproteins remain largely unknown. We investigated the role of two KSHV envelope glycoproteins, KSHV complement control protein (KCP) and K8.1, in viral infection in various cell types in vitro and in vivo. Using our newly generated anti-KCP antibodies, previously characterized anti-K8.1 antibodies, and recombinant mutant KSHV viruses lacking KCP, K8.1, or both, we demonstrated the presence of KCP and K8.1 on the surface of both virions and KSHV-infected cells. We showed that KSHV lacking KCP and/or K8.1 remained infectious in KSHV-susceptible cell lines, including epithelial, endothelial, and fibroblast, when compared to wild-type recombinant KSHV. We also provide the first evidence that KSHV lacking K8.1 or both KCP and K8.1 can infect human B cells in vivo in a humanized mouse model. Thus, these results suggest that neither KCP nor K8.1 is required for KSHV infection of various host cell types and that these glycoproteins do not determine KSHV cell tropism. IMPORTANCE: Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic human gamma-herpesvirus associated with the endothelial malignancy Kaposi sarcoma and the lymphoproliferative disorders primary effusion lymphoma and multicentric Castleman disease. Determining how KSHV glycoproteins such as complement control protein (KCP) and K8.1 contribute to the establishment, persistence, and transmission of viral infection will be key for developing effective anti-viral vaccines and therapies to prevent and treat KSHV infection and KSHV-associated diseases. Using newly generated anti-KCP antibodies, previously characterized anti-K8.1 antibodies, and recombinant mutant KSHV viruses lacking KCP and/or K8.1, we show that KCP and K8.1 can be found on the surface of both virions and KSHV-infected cells. Furthermore, we show that KSHV lacking KCP and/or K8.1 remains infectious to diverse cell types susceptible to KSHV in vitro and to human B cells in vivo in a humanized mouse model, thus providing evidence that these viral glycoproteins are not required for KSHV infection.
Subject(s)
Herpesvirus 8, Human , Sarcoma, Kaposi , Viral Envelope Proteins , Viral Proteins , Herpesvirus 8, Human/genetics , Herpesvirus 8, Human/physiology , Humans , Animals , Mice , Viral Proteins/metabolism , Viral Proteins/genetics , Sarcoma, Kaposi/virology , Viral Envelope Proteins/metabolism , Viral Envelope Proteins/genetics , Cell Line , Castleman Disease/virology , Castleman Disease/metabolism , Herpesviridae Infections/virology , Herpesviridae Infections/metabolism , HEK293 Cells , Endothelial Cells/virologyABSTRACT
BACKGROUND: Kaposi sarcoma (KS) is a multicentric vascular and lymphatic neoplasm caused by human herpesvirus 8 (HHV-8). It generally concerns the elderly and immunosuppressed population. Four major clinical types of KS have been described. The most common subtype is Classical KS (CKS). OBJECTIVES: Our retrospective study aimed to better define prognostic subgroups among patients with CKS, which is the most common in our country. METHOD: Between 2014 and 2020, 43 patients with CKS were treated with local excision, radiotherapy and chemotherapy. Reviewed information included demographics, clinical features, laboratory findings, treatment responses and overall survival. RESULTS: During the follow-up, eight patients (18.6%) died of CKS. The complete response rate was 46.5%, partial response and stable disease 51.2%, and progressive disease 2.3% of all patients. Gender, haemoglobin level at diagnosis, and disseminated involvement were prognostic factors affecting survival in all patients. CONCLUSION: We confirmed that male gender, low haemoglobin levels, and disseminated involvement are associated with poor prognosis in CKS patients. It is the only Turkish study in which prognostic analysis was performed for this rare cancer.
Subject(s)
Sarcoma, Kaposi , Skin Neoplasms , Humans , Sarcoma, Kaposi/therapy , Male , Female , Retrospective Studies , Middle Aged , Prognosis , Aged , Skin Neoplasms/pathology , Skin Neoplasms/therapy , Skin Neoplasms/mortality , Adult , Aged, 80 and over , Sex Factors , Turkey/epidemiology , Survival Rate , Hemoglobins/analysis , Hemoglobins/metabolismABSTRACT
During viral infection, the innate immune system utilizes a variety of specific intracellular sensors to detect virus-derived nucleic acids and activate a series of cellular signaling cascades that produce type I IFNs and proinflammatory cytokines and chemokines. Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic double-stranded DNA virus that has been associated with a variety of human malignancies, including Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman disease. Infection with KSHV activates various DNA sensors, including cGAS, STING, IFI16, and DExD/H-box helicases. Activation of these DNA sensors induces the innate immune response to antagonize the virus. To counteract this, KSHV has developed countless strategies to evade or inhibit DNA sensing and facilitate its own infection. This review summarizes the major DNA-triggered sensing signaling pathways and details the current knowledge of DNA-sensing mechanisms involved in KSHV infection, as well as how KSHV evades antiviral signaling pathways to successfully establish latent infection and undergo lytic reactivation.
Subject(s)
DNA, Viral , Herpesvirus 8, Human , Immunity, Innate , Signal Transduction , Herpesvirus 8, Human/genetics , Herpesvirus 8, Human/physiology , Humans , DNA, Viral/metabolism , Herpesviridae Infections/virology , Herpesviridae Infections/metabolism , Sarcoma, Kaposi/virology , Nucleotidyltransferases/metabolism , Host-Pathogen Interactions , Animals , Membrane Proteins/metabolism , Nuclear Proteins , PhosphoproteinsABSTRACT
Kaposi's sarcoma (KS) may derive from Kaposi's sarcoma herpesvirus (KSHV)-infected human mesenchymal stem cells (hMSCs) that migrate to sites characterized by inflammation and angiogenesis, promoting the initiation of KS. By analyzing the RNA sequences of KSHV-infected primary hMSCs, we have identified specific cell subpopulations, mechanisms, and conditions involved in the initial stages of KSHV-induced transformation and reprogramming of hMSCs into KS progenitor cells. Under proangiogenic environmental conditions, KSHV can reprogram hMSCs to exhibit gene expression profiles more similar to KS tumors, activating cell cycle progression, cytokine signaling pathways, endothelial differentiation, and upregulating KSHV oncogenes indicating the involvement of KSHV infection in inducing the mesenchymal-to-endothelial (MEndT) transition of hMSCs. This finding underscores the significance of this condition in facilitating KSHV-induced proliferation and reprogramming of hMSCs towards MEndT and closer to KS gene expression profiles, providing further evidence of these cell subpopulations as precursors of KS cells that thrive in a proangiogenic environment.