Search Results (33)

AIDS-related malignant lymphomas (ARLs) are the lymphomas that develop in association with HIV infection. According to the introduction of combination antiretroviral therapy (cART), the life expectancy of People Living with HIV (PLWH) has markedly improved; however, approximately one-third of PLWH have passed away from the complications of malignancies, even in well-controlled PLWH. HIV itself is not tumorigenic, and most of these tumors are due to co-infection with oncogenic viruses. γ-herpes viruses (Epstein–Barr virus: EBV and Kaposi sarcoma-associated herpesvirus: KSHV) are the most significant risk factors for ARLs. Immunodeficiency, chronic inflammation, accelerated aging, and genetic instability caused by HIV infection, as well as HIV accessory molecules, are thought to promote lymphomagenesis. The prognosis of ARLs is comparable to that of non-HIV cases in the cART era. Intensive chemotherapy with autologous stem cell transplantation is also available for relapsed/refractory ARLs. Since the early stage of HIV infection has no symptoms, significant numbers of HIV-infected individuals have not noticed HIV infection until the onset of AIDS (so-called Ikinari AIDS). Since the ratio of these patients is more than 30% in Japan, hematologists should carefully consider the possibility of HIV infection in cases of lymphoma. Even in an era of cART, ARL remains a critical complication in PLWH, warranting continuous surveillance. Full article

Repressor element-1 silencing transcription factor or neuron-restrictive silencer factor (REST/NRSF) is an extensively studied neuronal gene regulator both in neuronal cells and non-neuronal cells. Even though the role of REST in host cellular gene regulation is well established, its role in the establishment of viral infections and its capability to stabilize and destabilize such viral infections are scarcely studied. Co-repressor and DNA modifiers are involved in REST-mediated repressive action of its target genes. The role of REST and co-repressors together or individually in the regulation of viral as well as host genes has been unraveled in a few viruses such as HIV and influenza as well as two of the herpesvirus family members, namely herpes simplex virus type 1 (HSV-1) and Kaposi’s sarcoma-associated herpesvirus (KSHV). Here, we summarize all such virus studies involved with REST to gain a better insight into REST biology in virus infections. We also focus on unraveling the possible RE-1 binding sites in the Epstein–Barr virus (EBV) genome, a well-known human oncogenic herpesvirus that is associated with infectious mononucleosis and neoplasms such as B-cell lymphomas, nasopharyngeal carcinoma, gastric carcinoma, etc. An in silico-based approach was employed towards the prediction of such possible RE-1 binding elements in the EBV genome. This review advances the present knowledge of REST in virus infection which will aid in future efforts towards a better understanding of how REST acts in herpesviruses and other viruses for their infections and pathogenesis. Full article

Kaposi sarcoma-associated herpes virus (KSHV), also known as human herpes virus 8 (HHV-8), is the primary etiologic cause of Kaposi sarcoma (KS) and KSHV Inflammatory Cytokine Syndrome (KICS). Patients with KICS demonstrate symptoms of systemic inflammation, high KSHV viral load, elevation of inflammatory markers, and increased mortality. Management requires rapid diagnosis, treatment of underlying HIV, direct treatment of KS, and addressing the hyperimmune response. While a case definition based on clinical presentation, imaging findings, laboratory values, KSHV viral load, and lymph-node biopsy has been proposed, some of the required investigations are frequently unavailable in resource-constrained settings. Due to these challenges, KICS likely remains underdiagnosed and undertreated in these settings. We report a case of a 19-year-old woman living with HIV, and intermittent adherence to her ART, who presented with hypotension and acute hypoxemic respiratory failure. She was found to have high KSHV and HIV viral loads, low CD4 count, anemia, thrombocytopenia, hypoalbuminemia, and elevated inflammatory markers. On bedside ultrasound, she was found to have bilateral pleural effusions, ascites, an enlarged spleen, and hyperechoic splenic lesions. The diagnosis of KICS was made based on this constellation of findings. Weighing the risk and benefits of steroid administration in KS patients, the patient was successfully treated by the continuation of ART and the initiation of paclitaxel chemotherapy and steroids. We propose an adapted case definition relevant to the resource-constrained context. Due to the dual burden of KSHV and HIV in sub-Saharan Africa, additional cases of KICS are likely, and this syndrome will contribute to the burden of early mortality in newly diagnosed HIV patients. Addressing the diagnostic and therapeutic challenges of KICS must be a part of the overall management of the HIV pandemic. Full article

Kaposi sarcoma (KS) is an AIDS-defining angio-proliferative malignancy, with the Kaposi sarcoma-associated herpes virus (KSHV) as its etiologic agent. Upon treatment with chemotherapy, a proportion of HIV-associated KS patients experience disease recurrence within a few months of completing treatment. We aimed at determining whether KSHV-specific adaptive immune responses were associated with KS recurrence upon complete remission. We conducted a prospective cohort study. The primary outcome was the recurrence of HIV-associated KS. An immunofluorescence assay was used to determine anti-KSHV antibodies, an enzyme-linked immunospot was conducted for T cell responses, PCR was carried out to determine KSHV status, and flow cytometry was used for CD4 counting and immunophenotyping. KSHV detection in PBMCs was high and not associated with KS recurrence-free survival (p = 0.29). Anti-KSHV antibody titers were high and not associated with recurrence-free survival (p = 0.63). KSHV-specific T cell responses dropped from baseline levels among individuals with recurrence, but the drop was not statistically significant. Individuals experiencing KS recurrence had a significantly higher proportion of T cell subsets expressing PD1, while those with sustained remission had a significant increase in CD4 T cell counts from baseline levels during the follow-up period (p = 0.02). Anti-KSHV antibodies are not a good correlate of protection from KS recurrence. T cells in individuals experiencing KS recurrence hadhigh PD1 expression, while an increase in CD4 counts was associated with sustained KS remission. Full article

Epigenetic reprogramming represents a series of essential events during many cellular processes including oncogenesis. The genome of Kaposi’s sarcoma-associated herpesvirus (KSHV), an oncogenic herpesvirus, is predetermined for a well-orchestrated epigenetic reprogramming once it enters into the host cell. The initial epigenetic reprogramming of the KSHV genome allows restricted expression of encoded genes and helps to hide from host immune recognition. Infection with KSHV is associated with Kaposi’s sarcoma, multicentric Castleman’s disease, KSHV inflammatory cytokine syndrome, and primary effusion lymphoma. The major epigenetic modifications associated with KSHV can be labeled under three broad categories: DNA methylation, histone modifications, and the role of noncoding RNAs. These epigenetic modifications significantly contribute toward the latent–lytic switch of the KSHV lifecycle. This review gives a brief account of the major epigenetic modifications affiliated with the KSHV genome in infected cells and their impact on pathogenesis. Full article

Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8, is the causative agent of Kaposi’s sarcoma, Castleman’s disease, and primary effusion lymphoma. Although the functions of the viral thymidine kinases (vTK) of herpes simplex virus-1/2 are well understood, that of KSHV ORF21 (an ortholog of vTK) is largely unknown. Here, we investigated the role of ORF21 in lytic replication and infection by generating two ORF21-mutated KSHV BAC clones: ORF21-kinase activity deficient KSHV (21KD) and stop codon-induced ORF21-deleted KSHV (21del). The results showed that both ORF21 mutations did not affect viral genome replication, lytic gene transcription, or the production of viral genome-encapsidated particles. The ORF21 molecule-dependent function, other than the kinase function of ORF21, was involved in the infectivity of the progeny virus. ORF21 was expressed 36 h after the induction of lytic replication, and endogenously expressed ORF21 was localized in the whole cytoplasm. Moreover, ORF21 upregulated the MEK phosphorylation and anchorage-independent cell growth. The inhibition of MEK signaling by U0126 in recipient target cells suppressed the number of progeny virus-infected cells. These suggest that ORF21 transmitted as a tegument protein in the progeny virus enhances the new infection through MEK up-regulation in the recipient cell. Our findings indicate that ORF21 plays key roles in the infection of KSHV through the manipulation of the cellular function. Full article

Herpesviruses are one of the most contagious DNA viruses that threaten human health, causing severe diseases, including, but not limited to, certain types of cancer and neurological complications. The overuse and misuse of anti-herpesvirus drugs are key factors leading to drug resistance. Therefore, targeting human herpesviruses with natural products is an attractive form of therapy, as it might improve treatment efficacy in therapy-resistant herpesviruses. Plant polyphenols are major players in the health arena as they possess diverse bioactivities. Hence, in this article, we comprehensively summarize the recent advances that have been attained in employing plant non-flavonoid polyphenols, such as phenolic acids, tannins and their derivatives, stilbenes and their derivatives, lignans, neolignans, xanthones, anthraquinones and their derivatives, curcuminoids, coumarins, furanocoumarins, and other polyphenols (phloroglucinol) as promising anti-herpesvirus drugs against various types of herpesvirus such as alpha-herpesviruses (herpes simplex virus type 1 and 2 and varicella-zoster virus), beta-herpesviruses (human cytomegalovirus), and gamma-herpesviruses (Epstein–Barr virus and Kaposi sarcoma-associated herpesvirus). The molecular mechanisms of non-flavonoid polyphenols against the reviewed herpesviruses are also documented. Full article

Space exploration has brought many challenges to human physiology. In order to evaluate and reduce possible pathological reactions triggered by space environments, we conducted bioinformatics analyses on the methylation data of the Mars 520 mission and human transcriptome data in the experiment simulating gravity changes. The results suggest that gene expression levels and DNA methylation levels were changed under the conditions of isolation and gravity changes, and multiple viral infection-related pathways were found in the enrichment analysis results of changed genes including Epstein Barr virus (EBV) infection, Hepatitis B virus (HBV) infection, Herpes simplex virus (HSV) infection and Kaposi’s sarcoma-associated herpesvirus (KHSV) infection. In this study, we found that Epigallocatechin-3-gallate (EGCG) and vitamin D are helpful in reducing viral infection risk. In addition, the causal associations between nutrients and viral infections were calculated using Two sample Mendelian Randomization (2SMR) method, the results indicated that vitamin D can reduce EBV infection and HBV infection risk. In summary, our study suggests that space environments increase the risk of human viral infection, which may be reduced by supplementing EGCG and vitamin D. These results can be used to formulate medical plans for astronauts, which have practical application value for future space exploration. Full article

Kaposi’s sarcoma (KS) is a heterogeneous angioproliferative tumor that generally arises in the skin. At least four forms of this disease have been described, with the ‘HIV’-related form being the most aggressive and can involve mucosae or visceral organs. Three quarters of KS cases occur in sub-Saharan Africa (SSA) as geographic variation is explained by the disparate prevalence of KS-associated herpes virus (KSHV), which is the underlying cause of this disease. It can infect endothelial and/or mesenchymal cells that consequently transdifferentiate to an intermediate state. KSHV establishes a latent phase in host cells in which latency proteins and various non-coding RNAs (ncRNAs) play a complex role in proliferation and angiogenesis. It also undergoes periods of sporadic lytic reactivation triggered by various biological signals in which lytic stage proteins modulate host cell signaling pathways and are key in KS progression. Complex interactions with the microenvironment with production of inflammatory cytokines with paracrine signaling is a standout feature of KS development and maintenance. KSHV impairs the immune response by various mechanisms such as the degradation of a variety of proteins involved in immune response or binding to cellular chemokines. Treatment options include classical chemotherapy, but other novel therapies are being investigated. Full article

Numerous large DNA viruses have evolved sophisticated countermeasures to hijack the premature programmed cell death of host cells post-infection, including the expression of proteins homologous in sequence, structure, or function to cellular Bcl-2 proteins. Kaposi sarcoma herpes virus (KSHV), a member of the gammaherpesvirinae, has been shown to encode for KsBcl-2, a potent inhibitor of Bcl-2 mediated apoptosis. KsBcl-2 acts by directly engaging host pro-apoptotic Bcl-2 proteins including Bak, Bax and Bok, the BH3-only proteins; Bim, Bid, Bik, Hrk, Noxa and Puma. Here we determined the crystal structures of KsBcl-2 bound to the BH3 motif of pro-apoptotic proteins Bid and Puma. The structures reveal that KsBcl-2 engages pro-apoptotic BH3 motif peptides using the canonical ligand binding groove. Thus, the presence of the readily identifiable conserved BH1 motif sequence “NWGR” of KsBcl-2, as well as highly conserved Arg residue (R86) forms an ionic interaction with the conserved Asp in the BH3 motif in a manner that mimics the canonical ionic interaction seen in host Bcl-2:BH3 motif complexes. These findings provide a structural basis for KSHV mediated inhibition of host cell apoptosis and reveal the flexibility of virus encoded Bcl-2 proteins to mimic key interactions from endogenous host signalling pathways. Full article

Human herpesviruses (HHVs) are large DNA viruses with highly infectious characteristics. HHVs can induce lytic and latent infections in their host, and most of these viruses are neurotropic, with the capacity to generate severe and chronic neurological diseases of the peripheral nervous system (PNS) and central nervous system (CNS). Treatment of HHV infections based on strategies that include natural products-derived drugs is one of the most rapidly developing fields of modern medicine. Therefore, in this paper, we lend insights into the recent advances that have been achieved during the past five years in utilizing flavonoids as promising natural drugs for the treatment of HHVs infections of the nervous system such as alpha-herpesviruses (herpes simplex virus type 1, type 2, and varicella-zoster virus), beta-herpesviruses (human cytomegalovirus), and gamma-herpesviruses (Epstein–Barr virus and Kaposi sarcoma-associated herpesvirus). The neurological complications associated with infections induced by the reviewed herpesviruses are emphasized. Additionally, this work covers all possible mechanisms and pathways by which flavonoids induce promising therapeutic actions against the above-mentioned herpesviruses. Full article

Kaposi’s sarcoma (KS) is a vascular neoplasm Herpes Virus 8 (HHV8), which can affect the skin, mucous membranes and viscera. There is currently no standard treatment for KS; this study evaluated the efficacy and safety of Neodymium:YAG (Nd:YAG) laser 1064 nm treatment in patients with classic and HIV-associated KS. 15 patients with classic KS (group A) and 15 with epidemic KS (group B), with exclusively cutaneous localization, were treated with Nd:YAG laser 1064 nm. Four treatment sessions were performed at 4 weeks intervals. 24/30 (80%) of treated patients underwent clinical improvement. Better results have been obtained in HIV-positive patients, especially in terms of reduced lesion size and the flattening of elevated lesions. The 1064 nm Nd:YAG laser is effective and safe in the treatment of classic and epidemic KS, especially in patients with symptomatic, slow-progressing local disease, where other treatment options may be inappropriate. Full article

The tumor viruses human T-lymphotropic virus 1 (HTLV-1), hepatitis C virus (HCV), Merkel cell polyomavirus (MCPyV), high-risk human papillomaviruses (HR-HPVs), Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpes virus (KSHV) and hepatitis B virus (HBV) account for approximately 15% of all human cancers. Although the oncoproteins of these tumor viruses display no sequence similarity to one another, they use the same mechanisms to convey cancer hallmarks on the infected cell. Perturbed gene expression is one of the underlying mechanisms to induce cancer hallmarks. Epigenetic processes, including DNA methylation, histone modification and chromatin remodeling, microRNA, long noncoding RNA, and circular RNA affect gene expression without introducing changes in the DNA sequence. Increasing evidence demonstrates that oncoviruses cause epigenetic modifications, which play a pivotal role in carcinogenesis. In this review, recent advances in the role of host cell epigenetic changes in virus-induced cancers are summarized. Full article

Cancer is a global health problem associated with genetics and unhealthy lifestyles. Increasingly, pathogenic infections have also been identified as contributors to human cancer initiation and progression. Most pathogens (bacteria, viruses, fungi, and parasites) associated with human cancers are categorized as Group I human carcinogens by the International Agency for Research on Cancer, IARC. These pathogens cause carcinogenesis via three known mechanisms: persistent infection that cause inflammation and DNA damage, initiation of oncogene expression, and immunosuppression activity of the host. In this review, we discuss the carcinogenesis mechanism of ten pathogens, their implications, and some future considerations for better management of the disease. The pathogens and cancers described are Helicobacter pylori (gastric cancer), Epstein-Barr virus (gastric cancer and lymphoma), Hepatitis B and C viruses (liver cancer), Aspergillus spp. (liver cancer), Opisthorchis viverrine (bile duct cancer), Clonorchis sinensis (bile duct cancer), Fusobacterium nucleatum (colorectal cancer), Schistosoma haematobium (bladder cancer); Human Papillomavirus (cervical cancer), and Kaposi’s Sarcoma Herpes Virus (Kaposi’s sarcoma). Full article

Kaposi’s sarcoma-associated herpesvirus (KSHV) causes Kaposi’s sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman disease. Although capsid formation and maturation in the alpha-herpesvirus herpes simplex virus 1 are well understood, these processes in KSHV remain unknown. The KSHV ORF7, encoding the viral terminase (DNA cleavage and packaging protein), is thought to contribute to capsid formation; however, functional information is lacking. Here, we investigated the role of ORF7 during KSHV lytic replication by generating two types of ORF7 knock-out (KO) mutants (frameshift-induced and stop codon-induced ORF7 deficiency), KSHV BAC16, and its revertants. The results revealed that both ORF7-KO KSHVs showed significantly reduced viral production but there was no effect on lytic gene expression and viral genome replication. Complementation assays showed virus production from cells harboring ORF7-KO KSHV could be recovered by ORF7 overexpression. Additionally, exogenously expressed ORF7 partially induced nuclear relocalization of the other terminase components, ORF29 and ORF67.5. ORF7 interacted with both ORF29 and ORF67.5, whereas ORF29 and ORF67.5 failed to interact with each other, suggesting that ORF7 functions as a hub molecule in the KSHV terminase complex for interactions between ORF29 and ORF67.5. These findings indicate that ORF7 plays a key role in viral replication, as a component of terminase. Full article