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Kaposi’s sarcoma-associated herpesvirus (KSHV) is associated with three malignancies— Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman’s disease (MCD). Central to the pathogenesis of these diseases is the KSHV viral life cycle, which is composed of a quiescent latent phase and a replicative lytic phase. While the establishment of latency enables persistent KSHV infection and evasion of the host immune system, lytic replication is essential for the dissemination of the virus between hosts and within the host itself. The transition between these phases, known as lytic reactivation, is controlled by a complex set of environmental, host, and viral factors. The effects of these various factors converge on the regulation of two KSHV proteins whose functions facilitate each phase of the viral life cycle—latency-associated nuclear antigen (LANA) and the master switch of KSHV reactivation, replication and transcription activator (RTA). This review presents the current understanding of how the transition between the phases of the KSHV life cycle is regulated, how the various phases contribute to KSHV pathogenesis, and how the viral life cycle can be exploited as a therapeutic target.

[...]cGAS deficiency does not affect SeV-induced IFNβ production [13]. [...]although cGAS restricts replication of some RNA viruses, it is not required for RNA virus-induced type I IFN responses. On the contrary, infection of some RNA viruses was seen to up-regulate expression of STING at both mRNA and protein levels [21]. [...]distinct and context-dependent mechanisms likely exist between STING-mediated antiviral responses to DNA versus RNA viruses. A recent study demonstrated that rather than induce IFN expression, STING initiates a global translation inhibition to restrict production of both viral and host proteins in a RIG-I/MDA5-dependent but MAVS-independent manner [11]. [...]recognition of RNA virus infection by RIG-I/MDA5 probably results in two distinct responses: one is mediated by MAVS to induce IFNs and cytokines, and the other is mediated by STING to inhibit translation. Two oncoviruses, human papillomavirus 18 (HPV18) and human adenovirus 5 (hAd5), have been shown to inhibit STING activity using their viral oncoproteins E7 and E1A, respectively [28]. [...]the Hepatitis B virus (HBV) polymerase was found to bind STING and attenuate its K63-linked polyubiquitination and function [29].

Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8, is the etiologic agent underlying Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. This human gammaherpesvirus was discovered in 1994 by Drs. Yuan Chang and Patrick Moore. Today, there are over five thousand publications on KSHV and its associated malignancies. In this article, we review recent and ongoing developments in the KSHV field, including molecular mechanisms of KSHV pathogenesis, clinical aspects of KSHV-associated diseases, and current treatments for cancers associated with this virus.

Kaposi sarcoma (KS) gained public attention as an AIDS-defining malignancy; its appearance on the skin was a highly stigmatizing sign of HIV infection during the height of the AIDS epidemic. The widespread introduction of effective antiretrovirals to control HIV by restoring immunocompetence reduced the prevalence of AIDS-related KS, although KS does occur in individuals with well-controlled HIV infection. KS also presents in individuals without HIV infection in older men (classic KS), in sub-Saharan Africa (endemic KS) and in transplant recipients (iatrogenic KS). The aetiologic agent of KS is KS herpesvirus (KSHV; also known as human herpesvirus-8), and viral proteins can induce KS-associated cellular changes that enable the virus to evade the host immune system and allow the infected cell to survive and proliferate despite viral infection. Currently, most cases of KS occur in sub-Saharan Africa, where KSHV infection is prevalent owing to transmission by saliva in childhood compounded by the ongoing AIDS epidemic. Treatment for early AIDS-related KS in previously untreated patients should start with the control of HIV with antiretrovirals, which frequently results in KS regression. In advanced-stage KS, chemotherapy with pegylated liposomal doxorubicin or paclitaxel is the most common treatment, although it is seldom curative. In sub-Saharan Africa, KS continues to have a poor prognosis. Newer treatments for KS based on the mechanisms of its pathogenesis are being explored. Kaposi sarcoma is a rare cancer that typically presents with multiple pigmented skin lesions, but may take an aggressive course characterised by lesion ulceration, oedema and visceral organ involvement. This Primer describes the epidemiology, clinical features, cellular mechanisms and management of the main forms of Kaposi sarcoma.

Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is associated with KS, primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD). To ensure its own survival and propagation, KSHV employs an extensive network of viral proteins to subvert the host immune system, resulting in lifelong latent infection. Modulation of cellular and systemic immune defenses allows KSHV to persist in the host, which may eventually lead to the progression of KSHV-associated cancers. Due to KSHV's reliance on modifying immune responses to efficiently infect its host, immunotherapy is an attractive option for treating KSHV-associated malignancies. In this review, we will focus on the mechanisms by which KSHV evades the immune system and the current immune-related clinical strategies to treat KSHV-associated disease.

  [...]in addition to being etiologic agents of cancer, viruses have also provided us with the tools to understand the mechanisms that underlie the development of human cancer as well as basic cell biology. The goal of our program is to investigate cancers that disproportionally affect low-income countries, many of which are viral cancers. [...]far, our achievements have been in cancer diagnosis, basic and translational research, as well as preclinical studies, which represent the cornerstone for treatment.

Host cells sense viral infection through pattern recognition receptors (PRRs), which detect pathogen-associated molecular patterns (PAMPs) and stimulate an innate immune response. PRRs are localized to several different cellular compartments and are stimulated by viral proteins and nucleic acids. PRR activation initiates signal transduction events that ultimately result in an inflammatory response. Human tumour viruses, which include Kaposi's sarcoma-associated herpesvirus, Epstein–Barr virus, human papillomavirus, hepatitis C virus, hepatitis B virus, human T-cell lymphotropic virus type 1 and Merkel cell polyomavirus, are detected by several different PRRs. These viruses engage in a variety of mechanisms to evade the innate immune response, including downregulating PRRs, inhibiting PRR signalling, and disrupting the activation of transcription factors critical for mediating the inflammatory response, among others. This review will describe tumour virus PAMPs and the PRRs responsible for detecting viral infection, PRR signalling pathways, and the mechanisms by which tumour viruses evade the host innate immune system. This article is part of the themed issue ‘Human oncogenic viruses’.

Human gammaherpesviruses comprise of Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), and are oncogenic viruses that cause life-long infections. The gammaherpesviruses utilize an extensive virus-host interaction network for facilitating viral replication, whereby virus-encoded proteins modulate host processes. Thus, identifying targets of viral proteins that aid in gammaherpesviral replication will help develop therapies to combat these viruses. We identified that host proteins DDX5 and DDX17 interact with gammaherpesviral protein kinases, KSHV-encoded vPK and EBV-encoded BGLF4. We found that DDX5 and DDX17 are required for gammaherpesviral lytic reactivation and loss of both DDX5 and DDX17 decreased KSHV and EBV lytic reactivation. Depletion of DDX5 and DDX17 lowered the transcription of KSHV RTA, the key viral gene that drives the lytic replication cascade, due to reduced occupancy of Brg1, a chromatin remodeler, at the RTA promoter. Consequently, inhibition of Brg1 decreased gammaherpesviral lytic reactivation. Here we demonstrate how gammaherpesviruses hijack the function of two host proteins to promote their lytic replication cycle.

Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic gammaherpesvirus and the etiological agent of several diseases. These include the malignancies Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD), as well as the inflammatory disorder KSHV inflammatory cytokine syndrome (KICS). The KSHV lifecycle is characterized by two phases: a default latent phase and a lytic replication cycle. During latency, the virus persists as an episome within host cells, expressing a limited subset of viral genes to evade immune surveillance while promoting cellular transformation. The lytic phase, triggered by various stimuli, results in the expression of the full viral genome, production of infectious virions, and modulation of the tumor microenvironment. Both phases of the KSHV lifecycle play crucial roles in driving viral pathogenesis, influencing oncogenesis and immune evasion. This review dives into the intricate world of the KSHV lifecycle, focusing on the molecular mechanisms that drive its latent and lytic phases, their roles in disease progression, and current therapeutic strategies.