kshv infection
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Author(s):  
Wen-ying Long ◽  
Guo-hua Zhao ◽  
Yao Wu

Kaposi’s sarcoma-associated herpesvirus (KSHV) has two life cycle modes: the latent and lytic phases. The endoplasmic reticulum (ER) is the site for KSHV production. Furthermore, ER stress can trigger reactivation of KSHV. Little is known about the nature of the ER factors that regulate KSHV replication. Atlastin proteins (ATLs which include ATL1, ATL2, and ATL3) are large dynamin-related GTPases that control the structure and the dynamics of the ER membrane. Here, we show that ATLs can regulate KSHV lytic activation and infection. Overexpression of ATLs enhances KSHV lytic activation, whereas ATLs silence inhibits it. Intriguingly, we find that silencing of ATLs impairs the response of cells to ER stress, and ER stress can promote the lytic activation of KSHV. Our study establishes that ATLs plays a critically regulatory role in KSHV infection, thus expanding the known scope of biological processes controlled by ATLs to include KSHV infection.


2022 ◽  
Vol 12 ◽  
Author(s):  
Melissa J. Blumenthal ◽  
Humaira Lambarey ◽  
Abeen Chetram ◽  
Catherine Riou ◽  
Robert J. Wilkinson ◽  
...  

In South Africa, the Coronavirus Disease 2019 (COVID-19) pandemic is occurring against the backdrop of high Human Immunodeficiency Virus (HIV), tuberculosis and non-communicable disease burdens as well as prevalent herpesviruses infections such as Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV). As part of an observational study of adults admitted to Groote Schuur Hospital, Cape Town, South Africa during the period June–August 2020 and assessed for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, we measured KSHV serology and KSHV and EBV viral load (VL) in peripheral blood in relation to COVID-19 severity and outcome. A total of 104 patients with PCR-confirmed SARS-CoV-2 infection were included in this study. 61% were men and 39% women with a median age of 53 years (range 21–86). 29.8% (95% CI: 21.7–39.1%) of the cohort was HIV positive and 41.1% (95% CI: 31.6–51.1%) were KSHV seropositive. EBV VL was detectable in 84.4% (95% CI: 76.1–84.4%) of the cohort while KSHV DNA was detected in 20.6% (95% CI: 13.6–29.2%), with dual EBV/KSHV infection in 17.7% (95% CI: 11.1–26.2%). On enrollment, 48 [46.2% (95% CI: 36.8–55.7%)] COVID-19 patients were classified as severe on the WHO ordinal scale reflecting oxygen therapy and supportive care requirements and 30 of these patients [28.8% (95% CI: 20.8–38.0%)] later died. In COVID-19 patients, detectable KSHV VL was associated with death after adjusting for age, sex, HIV status and detectable EBV VL [p = 0.036, adjusted OR = 3.17 (95% CI: 1.08–9.32)]. Furthermore, in HIV negative COVID-19 patients, there was a trend indicating that KSHV VL may be related to COVID-19 disease severity [p = 0.054, unstandardized co-efficient 0.86 (95% CI: –0.015–1.74)] in addition to death [p = 0.008, adjusted OR = 7.34 (95% CI: 1.69–31.49)]. While the design of our study cannot distinguish if disease synergy exists between COVID-19 and KSHV nor if either viral infection is indeed fueling the other, these data point to a potential contribution of KSHV infection to COVID-19 outcome, or SARS-CoV-2 infection to KSHV reactivation, particularly in the South African context of high disease burden, that warrants further investigation.


2022 ◽  
Vol 19 (1) ◽  
Author(s):  
Xin Zhang ◽  
Yiyun Xu ◽  
Yi Li ◽  
Huangbo Yuan ◽  
Zhenqiu Liu ◽  
...  

Abstract Background Kaposi’s sarcoma-associated herpes virus (KSHV) prevalence and risk factors exhibit considerable variations across populations in different geographic regions. Determinants and the transmission routes of KSHV infection are uncertain. We seek to identify the possible risk factors and the transmission routes of KSHV infection in non-endemic areas. Methods We collected annual cases and seroprevalence of KSHV and herpes simplex virus type 2 (HSV-2) from the NHANES III sampled individuals from the US general population (1988–1994). We included 13,179 and 10,720 individuals with available remaining serum samples of KSHV and HSV-2. Logistic regression was employed to explore potential risk factors for the seropositivity. Results The seroprevalence was 2.05% for KSHV infection and 31.03% for HSV2 infection among this population. All risk factors of sexual behaviors included were strongly associated with HSV-2 positive, however, only MSM had an approximately fivefold increased risk of KSHV infection (OR = 4.71; 95%CI 1.61 11.30). Mexican Americans (2.51%) and older (chi-squaretrend =  − 6.71, P < 0.001) individuals had a higher risk of KSHV infection. After adjustment, individuals with higher level of education and economic status had lower KSHV infection. Conclusions In non-endemic areas, KSHV transmission may be related to sexual activity in men, especially in male homosexuals. Higher education level and economic status are protective factors for KSHV infection.


2021 ◽  
Author(s):  
Mariel Kleer ◽  
Grant MacNeil ◽  
Nancy Adam ◽  
Eric S. Pringle ◽  
Jennifer A. Corcoran

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the cause of several human cancers including the endothelial cell (EC) malignancy, Kaposi’s sarcoma. Unique KSHV genes absent from other human herpesvirus genomes, the “K-genes”, are important for KSHV replication and pathogenesis. Among these, the kaposin transcript is highly expressed in all phases of infection, but its complex polycistronic nature has hindered functional analysis to date. At least three proteins are produced from the kaposin transcript: Kaposin A (KapA), B (KapB), and C (KapC). To determine the relative contributions of kaposin proteins during KSHV infection, we created a collection of mutant viruses unable to produce kaposin proteins individually or in combination. In previous work, we showed KapB alone recapitulated the elevated proinflammatory cytokine transcripts associated with KS via the disassembly of RNA granules called processing bodies (PBs). Using the new ΔKapB virus, we showed that KapB was necessary for this effect during latent KSHV infection. Moreover, we observed that despite the ability of all kaposin-deficient latent iSLK cell lines to produce virions, all displayed low viral episome copy number, a defect that became more pronounced after primary infection of naïve ECs. For ΔKapB, provision of KapB in trans failed to complement the defect, suggesting a requirement for the kaposin locus in cis . These findings demonstrate that our panel of kaposin-deficient viruses enables precise analysis of the respective contributions of individual kaposin proteins to KSHV replication. Moreover, our mutagenesis approach serves as a guide for the functional analysis of other complex multicistronic viral loci. Importance Kaposi’s sarcoma-associated herpesvirus (KSHV) expresses high levels of the kaposin transcript during both latent and lytic phases of replication. Due to its repetitive, GC-rich nature and polycistronic coding capacity, until now no reagents existed to permit a methodical analysis of the role of individual kaposin proteins in KSHV replication. We report the creation of a panel of recombinant viruses and matched producer cell lines that delete kaposin proteins individually or in combination. We demonstrate the utility of this panel by confirming the requirement of one kaposin translation product to a key KSHV latency phenotype. This study describes a new panel of molecular tools for the KSHV field to enable precise analysis of the roles of individual kaposin proteins during KSHV infection.


2021 ◽  
Author(s):  
Nedaa Alomari ◽  
Farizeh Aalasm ◽  
Romina Nabiee ◽  
Jesus Ramirez Castano ◽  
Jennifer Totonchy

AbstractKaposi’s sarcoma-associated herpesvirus (KSHV) extensively manipulates the host immune system and the cytokine milieu, and cytokines are known to influence the progression of KSHV-associated diseases. However, the precise role of cytokines in the early stages of KSHV infection remains undefined. Here, using our unique model of KSHV infection in tonsil lymphocytes, we investigate the influence of host cytokines on the establishment of KSHV infection in B cells. Our data demonstrate that KSHV manipulates the host cytokine microenvironment during early infection and susceptibility generally associated with downregulation of multiple cytokines. However, we show that IL-21 signaling promotes KSHV infection by promoting both plasma cell numbers and increasing KSHV infection in plasma cells. Our data reveal that IL-21 producing T cells, particularly Th17/Tc17 and central memory CD8+ T cells may represent immunological factors that modulate host-level susceptibility to KSHV infection. These results suggest that IL-21 plays a significant role in the early stages of KSHV infection in the human immune system and may represent a novel mechanism to be further explored in the context of preventing KSHV transmission.Author SummaryVery little is known about how KSHV is transmitted and how it initially establishes infection in a new human host and this lack of information limits our ability to prevent KSHV-associated cancers by limiting its person-to-person transmission. Saliva is thought to be the primary route of person-to-person transmission for KSHV, making the tonsil a likely first site for KSHV replication in a new human host. In particular, the tonsil is likely to be the first place KSHV is able to enter B cells, which are thought to be a major site of persistent infection. Our previous work identified plasma cells as a highly targeted cell type in early KSHV infection in cultured cells from human tonsil. In this study, we show that the human cytokine IL-21 promotes both overall KSHV infection and the establishment of infection in plasma cells. We also investigate the immunological mechanisms underlying this effect. Our results demonstrate that IL-21 and IL-21-producing cells are a novel factor that influences the initial establishment of KSHV infection in humans.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Dongdong Cao ◽  
Shuyuan Wu ◽  
Xiaolu Wang ◽  
Ying Li ◽  
Huiling Xu ◽  
...  

Abstract Background The cancer caused by Kaposi’s sarcoma-associated herpesvirus (KSHV) infection is one of the major causes of death in AIDS patients. Some patients have neurological symptoms, which appear to be associated with KSHV infection, based on the neurotropic tendency of this virus in recent years. The objectives of this study were to investigate the effects of KSHV infection on neuronal SH-SY5Y cells and to identify differentially expressed genes. Methods KSHV was collected from islk.219 cells. Real-time PCR was used to quantify KSHV copy numbers. KSHV was used to infect SH-SY5Y cells. The KSHV copy number in the supernatants and mRNA levels of latency-associated nuclear antigen (LANA), ORF26, K8.1 A, and replication and transcriptional activator (RTA) were detected by real-time PCR. Proteins were detected by immunohistochemistry. The effect of KSHV infection on cell proliferation was detected by MTT and Ki-67 staining. Cell migration was evaluated by Transwell and wound healing assays. The cell cycle was analyzed by flow cytometry. The expression of CDK4, CDK5, CDK6, cyclin D1, and p27 were measured by western blotting. The levels of cell cycle proteins were re-examined in LANA-overexpressing SH-SY5Y cells. Transcriptome sequencing was used to identify differentially expressed genes in KSHV-infected cells. The levels of Notch signaling pathway proteins were measured by western blotting. RNA interference was used to silence Notch1 and proliferation were analyzed again. Results SH-SY5Y cells were successfully infected with KSHV, and they maintained the ability to produce virions. KSHV-infected SH-SY5Y expressed LANA, ORF26, K8.1 A, and RTA. After KSHV infection, cell proliferation was enhanced, but cell migration was suppressed. KSHV infection accelerated the G0/G1 phase. CDK4, CDK5, CDK6, and cyclin D1 expression was increased, whereas p27 expression was decreased. After LANA overexpression, CDK4, CDK6 and cyclin D1 expression was increased. Transcriptome sequencing showed that 11,258 genes were upregulated and 1,967 genes were downregulated in KSHV-infected SH-SY5Y. The Notch signaling pathway played a role in KSHV infection in SH-SY5Y, and western blots confirmed that Notch1, NICD, RBP-Jĸ and Hes1 expression was increased. After silencing of Notch1, the related proteins and cell proliferation ability were decreased. Conclusions KSHV infected SH-SY5Y cells and promoted the cell proliferation. KSHV infection increased the expression of Notch signaling pathway proteins, which may have been associated with the enhanced cell proliferation.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tingting Li ◽  
Shou-Jiang Gao

AbstractKaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic gammaherpesvirus associated with several human cancers. KSHV infection and KSHV-induced anabolic cell proliferation and cellular transformation depend on reprogramming of cellular metabolic pathways, which provide the building blocks and energy for the growth of both the virus and the infected cells. Furthermore, KSHV dysregulates numerous metabolic sensors including mTOR, AMPK, CASTOR1 and sirtuins to maintain cellular energetic homeostasis during infection and in KSHV-induced cancers. In this review, we summarize the recent advances in the understanding of KSHV hijacking of metabolic pathways and sensors, providing insights into the molecular basis of KSHV infection and KSHV-induced oncogenesis. In addition, we highlight the critical metabolic targets and sensors for developing potential new therapies against KSHV infection and KSHV-induced cancers.


2021 ◽  
Author(s):  
Xin Zhang ◽  
Yiyun Xu ◽  
Yi Li ◽  
Huangbo Yuan ◽  
Zhenqiu Liu ◽  
...  

Abstract Background Kaposi’s sarcoma-associated herpes virus (KSHV) prevalence and risk factors exhibit considerable variations across populations in different geographic regions. Determinants and the transmission routes of KSHV infection are uncertain. We seek to identify the possible risk factors and the transmission routes of KSHV infection in non-endemic areas.Methods We collected annual cases and seroprevalence of KSHV and herpes simplex virus type 2 (HSV-2) from the NHANES III sampled individuals from the US general population (1988-1994). We included 13179 and 10720 individuals with available remaining serum samples of KSHV and HSV-2. Logistic regression were employed to explore potential risk factors for the seropositivity.Results The seroprevalence was 2.05% for KSHV infection and 31.03% for HSV2 infection among this population. All risk factors of sexual behaviors included were strongly associated with HSV-2 positive, however, only MSM had an approximately fivefold increased risk of KSHV infection (OR=4.71; 95%CI 1.61 11.30). Mexican Americans (2.51%) and older (chi-sqauretrend=-6.71, P<0.001) individuals had a higher risk of KSHV infection. After adjustment, individuals with higher level of education and economic status had lower KSHV infection.Conclusions In non-endemic areas, KSHV transmission may be related to sexual activity in men, especially in male homosexuals. Higher education level and economic status are protective factors for KSHV infection.


2021 ◽  
Vol 17 (9) ◽  
pp. e1009847
Author(s):  
Yao Ding ◽  
Weikang Chen ◽  
Zhengzhou Lu ◽  
Yan Wang ◽  
Yan Yuan

Increasing evidence suggests that Kaposi’s sarcoma (KS) arises from Kaposi’s sarcoma-associated herpesvirus (KSHV)-infected mesenchymal stem cells (MSCs) through mesenchymal-to-endothelial transition (MEndT). KSHV infection promotes MSC differentiation of endothelial lineage and acquisition of tumorigeneic phenotypes. To understand how KSHV induces MEndT and transforms MSCs to KS cells, we investigated the mechanism underlying KSHV-mediated MSC endothelial lineage differentiation. Like embryonic stem cells, MSC differentiation and fate determination are under epigenetic control. Prospero homeobox 1 (PROX1) is a master regulator that controls lymphatic vessel development and endothelial differentiation. We found that the PROX1 gene in MSCs harbors a distinctive bivalent epigenetic signature consisting of both active marker H3K4me3 and repressive marker H3K27me3, which poises expression of the genes, allowing timely activation upon differentiation signals or environmental stimuli. KSHV infection effectively resolves the bivalent chromatin by decreasing H3K27me3 and increasing H3K4me3 to activate the PROX1 gene. vIL-6 signaling leads to the recruitment of MLL2 and SET1 complexes to the PROX1 promoter to increase H3K4me3, and the vGPCR-VEGF-A axis is responsible for removing PRC2 from the promoter to reduce H3K27me3. Therefore, through a dual signaling process, KSHV activates PROX1 gene expression and initiates MEndT, which renders MSC tumorigenic features including angiogenesis, invasion and migration.


2021 ◽  
Author(s):  
Daniel Macveigh-Fierro ◽  
Angelina Cicerchia ◽  
Ashley Cadorette ◽  
Vasudha Sharma ◽  
Mandy Muller

The role m6A modifications have increasingly been associated with diverse set of roles in modulating viruses and influencing the outcomes of viral infection. Here we report that the landscape of m6A deposition is drastically shifted during KSHV (Kaposi Sarcoma Associated herpesvirus) lytic infection for both viral and host transcripts. In line with previous reports, we also saw an overall decrease in host methylation in favor of viral mRNA along with 5' hypomethylation and 3' hypermethylation. During KSHV lytic infection, a major shift in overall mRNA abundance is driven by the viral endoribonuclease SOX, which induces the decay of greater than 70% of transcripts. Here, we reveal that Interlukin-6 (IL-6) mRNA, a well-characterized SOX-resistant transcript, is m6A modified during lytic infection. Furthermore, we show that this modification falls within the IL-6 SOX Resistance Element (SRE), an RNA element in IL-6 3' UTR that was previously shown to be sufficient for protection from SOX cleavage. We show that the presence of this m6A modification is essential to confer SOX resistance to the IL-6 mRNA. We next show that this modification recruits the m6A reader YTHDC2 and found that YTHDC2 is necessary for the escape of the IL-6 transcript. These results shed light on how the host cell has evolved to use RNA modifications to circumvent viral manipulation of RNA fate during KSHV infection.


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