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ABSTRACT This case involves a 52‐year‐old male, who underwent a deceased donor orthotopic liver transplant 7 months prior, presented with a 2‐week history of persistent fever, anemia, thrombocytopenia, and mild elevation of liver enzymes. Upon hospital admission, the patient was febbrile, alert and oriented, hemodynamically stable. Laboratory exams revealed worsening leukopenia, anemia, thrombocytopenia, hyponatremia, and elevated ferritin. On hospital day 5, the general condition of the patient rapidly deteriorated with dyspnea, asthenia, and worsening fever and pancytopenia.Computed tomography revealed splenomegaly and minimal bilateral pleural effusion. [ABSTRACT FROM AUTHOR]

Abstract Background We report the impact of HIV infection within a household on oral Kaposi’s sarcoma-associated herpesvirus (KSHV) shedding. Methods We enrolled 469 individuals from 90 households. Mouthwash rinse samples collected at three monthly visits were analyzed for KSHV DNA using quantitative polymerase chain reaction (qPCR). Generalized linear mixed effects logistic models were applied to analyze factors associated with KSHV ever shedding, and among shedders, always versus intermittent shedding. Linear mixed effects models were applied to models of KSHV viral loads. Intraclass correlation coefficients (ICCs) were calculated to assess the contribution of household-level factors to variations in shedding probabilities. Hotspot analyses of geospatial feature clusters were calculated using Getis-Ord Gi* statistic and visualized using inverse distance weighted interpolation. Results Analyses included 340 KSHV seropositive individuals, aged 3 + years, with qPCR results from 89 households. Forty households had 1 + persons living with HIV (PLWH), while 49 had none. Among participants, 149(44%) were KSHV ever shedders. Of 140 who shed KSHV at two or more visits, 34(24%) were always shedders. Increasing number of KSHV seropositive household members was significantly associated with ever shedding [Odds ratio(OR) (95% Confidence Interval(95%CI)):1.14(1.03,1.26);p = 0.013]. Among KSHV shedders, a statistically significant age-related trend was identified with 10–19 years being more likely to be always shedders (type III test p = 0.039) and to have higher viral loads (type III test p = 0.027). In addition, higher viral loads were significantly associated with increasing number of household members [coefficient(95%CI):0.06(0.01,0.12);p = 0.042], increasing number of KSHV seropositive members [coefficient(95%CI):0.08(0.01,0.15);p = 0.021], and living in households with 1 + PLWH [coefficient(95%CI):0.51(0.04,0.98);p = 0.033]. Always shedders exhibited higher viral loads than intermittent shedders [coefficient(95%CI):1.62(1.19,2.05);p

Background: Kaposi sarcoma (KS) is a cutaneous neoplasm of endothelial origin. The causative agent is the human herpes virus-8 (HHV-8) which, combined with an immune system impairment, causes cell proliferation. To date, high-quality evidence and treatment recommendations for the management of KS are confined to the acquired immune deficiency syndrome (AIDS)-related KS, while the clinical approach to the treatment of classic KS (CKS) is based on small retrospective case series and the experience of clinicians in selected referral centers. Materials and Methods: A search of the English literature was conducted through PubMed/MEDLINE databases for studies regarding CKS diagnosis, staging, and treatment, published between January 1990 and September 2023. Results: Overall, 122 out of 565 articles were selected. Based on the results of this literature review, we proposed indications regarding the recommended flow chart for diagnosis, staging, and follow-up of patients with CKS. We assess available evidences regarding topic, locoregional, and systemic treatments of CKS. We also provide a focus on novel treatment strategies and therapeutic approaches currently under evaluation in clinical trials. Conclusion: CKS is a rare disease and its management requires a multidisciplinary assessment. Treatment in referral centers and enrolment in clinical trials might impact on outcomes. [ABSTRACT FROM AUTHOR]

Background: We report the impact of HIV infection within a household on oral Kaposi's sarcoma-associated herpesvirus (KSHV) shedding. Methods: We enrolled 469 individuals from 90 households. Mouthwash rinse samples collected at three monthly visits were analyzed for KSHV DNA using quantitative polymerase chain reaction (qPCR). Generalized linear mixed effects logistic models were applied to analyze factors associated with KSHV ever shedding, and among shedders, always versus intermittent shedding. Linear mixed effects models were applied to models of KSHV viral loads. Intraclass correlation coefficients (ICCs) were calculated to assess the contribution of household-level factors to variations in shedding probabilities. Hotspot analyses of geospatial feature clusters were calculated using Getis-Ord Gi* statistic and visualized using inverse distance weighted interpolation. Results: Analyses included 340 KSHV seropositive individuals, aged 3 + years, with qPCR results from 89 households. Forty households had 1 + persons living with HIV (PLWH), while 49 had none. Among participants, 149(44%) were KSHV ever shedders. Of 140 who shed KSHV at two or more visits, 34(24%) were always shedders. Increasing number of KSHV seropositive household members was significantly associated with ever shedding [Odds ratio(OR) (95% Confidence Interval(95%CI)):1.14(1.03,1.26);p = 0.013]. Among KSHV shedders, a statistically significant age-related trend was identified with 10–19 years being more likely to be always shedders (type III test p = 0.039) and to have higher viral loads (type III test p = 0.027). In addition, higher viral loads were significantly associated with increasing number of household members [coefficient(95%CI):0.06(0.01,0.12);p = 0.042], increasing number of KSHV seropositive members [coefficient(95%CI):0.08(0.01,0.15);p = 0.021], and living in households with 1 + PLWH [coefficient(95%CI):0.51(0.04,0.98);p = 0.033]. Always shedders exhibited higher viral loads than intermittent shedders [coefficient(95%CI):1.62(1.19,2.05);p < 0.001], and viral loads increased with the number of visits where KSHV DNA was detected in saliva (type III test p < 0.001). Household-level factors attributed for 19% of the variability in KSHV shedding (ICC:0.191;p = 0.010). Geospatial analysis indicated overlapping hotspots of households with more KSHV seropositive individuals and KSHV shedders, distinct from areas where PLWH were clustered. Discussion: KSHV oral shedding is influenced by multiple factors at the individual, household, and regional levels. To mitigate ongoing KSHV transmission a comprehensive understanding of factors contributing to oral KSHV reactivation and transmission within households is needed. [ABSTRACT FROM AUTHOR]

Background An improved understanding of oral Kaposi sarcoma–associated herpesvirus (KSHV) viral dynamics could provide insights into transmission risk and guide vaccine development. Methods We evaluated KSHV oral shedding dynamics in Ugandan adults stratified by Kaposi sarcoma (KS) and human immunodeficiency virus (HIV) status. Participants were followed for ≥4 weeks, with daily home oral swab collection to quantify KSHV using polymerase chain reaction. Shedding rates were defined by number of days with KSHV DNA detected divided by total days with swabs and compared by group using hurdle models. Results Two hundred ninety-five participants were enrolled; median age was 35 years (range, 18–71 years), and 134 (45%) were male. KSHV was detected more frequently among participants with KS (HIV positive [HIV+]/KS+, 56/76 [74%]; HIV negative [HIV−]/KS+, 9/18 [50%]) than those without KS (HIV+/KS−, 36/125 [29%]; HIV−/KS−, 16/76 [21%]); odds of shedding did not differ significantly by HIV status. Among participants with KSHV detected, shedding rates did not differ significantly by group. Median per-participant viral loads among positive samples were lowest in HIV+/KS+ (3.1 log10 copies/mL) and HIV−/KS+ (3.3 log10 copies/mL) participants relative to HIV+/KS− (3.8 log10 copies/mL) and HIV−/KS− (4.0 log10 copies/mL) participants. All groups had participants with low viral load intermittent shedding and participants with high viral load persistent shedding. Within each group, individual KSHV shedding rate positively correlated with median KSHV log10 copies/mL, and episode duration positively correlated with peak viral load. Conclusions Oral KSHV shedding is highly heterogeneous across Ugandan adults with and without KS and HIV. Persistent shedding is associated with higher median viral loads regardless of HIV and KS status. [ABSTRACT FROM AUTHOR]

Background: Human herpesvirus 8 (HHV-8) is a critical causative agent behind Kaposi sarcoma (KS), an oncogenic disease with profound consequences in immunocompromised individuals. Studies suggested HHV-8 seroprevalence in healthy populations is uncommon, but comprehensive investigations within the Middle East region remain scarce. This study aimed to bridge this knowledge gap by meticulously assessing HHV-8 seroprevalence among healthy blood donors in Qatar, leveraging serological methodologies and PCR. Methods: We used sera samples collected from 621 healthy blood donors (median age = 36 years, IQR 30–43) from different nationalities residing in Qatar, mainly from the MENA region and Southeast Asia. All sera samples were tested for total anti-HHV-8 IgG antibodies using ELISA. The presence of lytic HHV-8 antibodies was confirmed by an immunofluorescence assay (IFA). Further, HHV-8 DNA was tested and quantitated by qRT-PCR. Results: ELISA detected anti-HHV-8 IgG total antibodies in 6.9 % [43/621, 95 %CI 5.2–9.2] of the tested samples. Subsequent testing by IFA revealed that 14 % [6/43, 95 %CI 3.6–24.3] of these anti-HHV-8 IgG were classified as HHV-8 lytic antibodies. This suggests that 0.97 % [6/621, 95 %CI 0.2–1.7] of these donors had a recent or ongoing active infection and viral replication. Only one seronegative Qatari blood donor had detectable HHV-8 DNA in his blood. No significant difference was observed between HHV-8 seropositivity and the demographic characteristics of the donors. Conclusion: Our study showed that HHV-8 prevalence in Qatar aligns closely with global reports. Moreover, our findings raise considerations regarding HHV-8’s potential transmission via transfusion, which suggests the value of routine HHV-8 screening, particularly for immunocompromised patients vulnerable to KS.

Background: Human Herpes Virus 8 (HHV-8) is involved in autoimmunity. However, its association with advanced liver disease has not been fully explained. Herein, the prevalence of HHV-8 viremia was assessed in Iranian liver transplant candidates with a confirmed diagnosis of cirrhosis. Methods: This cross-sectional study was conducted on 230 patients with cryptogenic cirrhosis, virus-related cirrhosis, and autoimmune hepatitis, as well as 140 healthy blood donors from April 2022 to September 2023. The HHV-8 IgG antibody concentration and viral load were evaluated via ELISA and RT‒PCR, respectively. Results: Anti-HHV-8 IgG antibodies were detected in 25 cirrhotic patients (10.8 %) and four healthy individuals (2.6 %) (p = 0.022). The majority of the seropositive patients had cryptogenic cirrhosis (20.4 %), followed by autoimmune hepatitis (13.1 %) and virus-related cirrhosis (4.7 %). The seropositivity of HHV-8 IgG antibody was significantly different among the etiologies of liver cirrhosis (p = 0.011). However, HHV-8 genomic DNA was not detected in the sera of the patients or healthy blood donors. Conclusion: The role of HHV-8 infection in the development of posttransplant diseases, together with the higher seroprevalence of HHV-8 antibodies in cirrhotic patients than in healthy individuals, highlights the importance of both primary and latent infections in liver transplantation. Therefore, serological and molecular screening of HHV-8 is highly suggested for liver transplant candidates and organ donors. The possibility of antibody-mediated epitope mimicry in cryptogenic and autoimmune groups with moderate HHV-8 antibody positivity and negative viral loads may account for the development of advanced liver diseases.

This qualitative sub-study investigated household practices affecting orally shed infections using Kaposi’s sarcoma-associated herpesvirus (KSHV) as a focus. Participants enrolled from 50 households in rural south-western Uganda were followed monthly up to three times. At enrolment, in-depth interviews were completed, and venous blood collected. KSHV seropositivity was defined as anti-KSHV antibody detection to any of 25 antigens by multiplex bead-based assay. Mouthwash samples from every visit were tested by qPCR and KSHV shedders defined as individuals with KSHV DNA detected. At least one KSHV seropositive person was in 48/49(98%) households. Among those, 79% had 1+ KSHV shedders including 45% with 1+ always shedders and 92% with 1+ intermittent shedders, not mutually exclusively. All respondents reported feeding infants with pre-masticated hard food/fruits and testing food/tea temperature. Temperature was tested by tasting, pouring tea on their hand, or touching the cup to their cheek. Some cooled food/tea using a utensil or blowing over it. Food sharing amongst children and adults and using the same dish was common practice. To treat colic pain, carers/mothers reported chewing herbs and spitting into the child’s mouth. Feeding and treatment practices did not vary by KSHV status. We identified potential KSHV transmission modes in rural Ugandan households.

Objectives. Human herpesvirus 8 (HHV8) is rarely studied in Congo, despite its prevalence in Africa. Among healthy individuals, HHV-8 does not always lead to a life-threatening infection; however, in immunocompromised individuals, it could lead to more severe disease. The distribution of HHV-8 genotypes varies depending on ethnicity and geographic region. Method. A prospective cross-sectional study included 265 samples from healthy blood donors from the National Blood Transfusion Center in Brazzaville, with an average age of 35 years, with extremes ranging from 18 to 60 years. After DNA extraction, a nested PCR was carried out for molecular detection, followed by genotyping by amplification of specific primers. Result. In this study, 4.9% were positive for molecular detection of HHV-8 DNA. All HHV-8 positive DNA samples that were subjected to genotyping by amplification with specific primers allowing discrimination of two major genotypes (A and B). Genotype A was identified in 5 (1.9%) samples and genotype B in 2 (0.7%) samples, indicating that both genotypes were predominant. The remaining viral DNA samples not identified as the major genotypes were classified as «indeterminate» and consisted of 6 (2.3%) samples. Conclusion: The results of the study suggest that Congo is an area where HHV-8 infection is endemic.

Human immunodeficiency virus type 1 (HIV-1) gradually destroys the CD4$ ^{+} $ T cells leading to immune system dysfunction. HIV-1 can result in acquired immunodeficiency syndrome (AIDS) if antiretroviral drugs are not used. HIV/AIDS patients are more vulnerable to opportunistic infections or cancers. Human herpesvirus 8 (HHV-8) targets B cells and causes an AIDS-related cancer known as kaposi sarcoma (KS). Numerous investigations have demonstrated co-infection instances between HIV-1 and HHV-8. In this research, we investigated the co-dynamics of HIV-1 and HHV-8 in vivo using a system of delay differential equations (DDEs). The model explained the interactions between uninfected CD4$ ^{+} $ T cells, latently/actively HIV-1-infected CD4$ ^{+} $ T cells, free HIV-1 particles, uninfected B cells, latently/actively HHV-8-infected B cells, and free HHV-8 particles. Eight distributed-time delays were incorporated into the model to account for the delays that arose during the generation of both actively and latently infected cells, the activation of latent reservoirs, and the maturation of freshly discharged virions. By examining the nonnegativity and boundedness of the solutions, we demonstrated that the model was both mathematically and biologically well-posed. We calculated the model's equilibria and threshold numbers. We studied the global asymptotic stability of the model's equilibria by building appropriate Lyapunov functionals and applying the Lyapunov-LaSalle asymptotic stability theorem. Numerical simulations were used to display the results. For the basic reproduction numbers of HHV-8 single-infection ($ R_{1} $) and HIV-1 single-infection ($ R_{2} $), sensitivity analysis was carried out. Comparing HIV-1 or HHV-8 single infections with co-infections of HHV-8 and HIV-1 was shown. It's interesting to note that we detected larger amounts of HHV-8 and HIV-1 when they co-infect than when they are infected alone. This outcome aligned with several findings seen in the literature. The effect of antiviral drugs and time delays on the co-dynamics of HIV-1 and HHV-8 was investigated. We found that the delay parameter and drug effectiveness both contributed to a decrease in the basic reproduction numbers, $ R_{1} $ and $ R_{2} $. Less treatment efficacies will be needed to keep the system at the infection-free equilibrium and remove HIV-1 and HHV-8 from the body if a model with time delays is employed.

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. [ABSTRACT FROM AUTHOR]

The cellular Notch signal transduction pathway is intimately associated with infections by Kaposi’s sarcoma-associated herpesvirus (KSHV) and other gamma-herpesviruses. RBP-Jk, the cellular DNA binding component of the canonical Notch pathway, is the key Notch downstream effector protein in virus-infected and uninfected animal cells. Reactivation of KSHV from latency requires the viral lytic switch protein, Rta, to form complexes with RBP-Jk on numerous sites within the viral DNA. Constitutive Notch activity is essential for KSHV pathophysiology in models of Kaposi’s sarcoma (KS) and Primary Effusion Lymphoma (PEL), and we demonstrate that Notch1 is also constitutively active in infected Vero cells. Although the KSHV genome contains >100 RBP-Jk DNA motifs, we show that none of the four isoforms of activated Notch can productively reactivate the virus from latency in a highly quantitative trans-complementing reporter virus system. Nevertheless, Notch contributed positively to reactivation because broad inhibition of Notch1-4 with gamma-secretase inhibitor (GSI) or expression of dominant negative mastermind-like1 (dnMAML1) coactivators severely reduced production of infectious KSHV from Vero cells. Reduction of KSHV production is associated with gene-specific reduction of viral transcription in both Vero and PEL cells. Specific inhibition of Notch1 by siRNA partially reduces the production of infectious KSHV, and NICD1 forms promoter-specific complexes with viral DNA during reactivation. We conclude that constitutive Notch activity is required for the robust production of infectious KSHV, and our results implicate activated Notch1 as a pro-viral member of a MAML1/RBP-Jk/DNA complex during viral reactivation. IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) manipulates the host cell oncogenic Notch signaling pathway for viral reactivation from latency and cell pathogenesis. KSHV reactivation requires that the viral protein Rta functionally interacts with RBP-Jk, the DNA-binding component of the Notch pathway, and with promoter DNA to drive transcription of productive cycle genes. We show that the Notch pathway is constitutively active during KSHV reactivation and is essential for robust production of infectious virus progeny. Inhibiting Notch during reactivation reduces the expression of specific viral genes yet does not affect the growth of the host cells. Although Notch cannot reactivate KSHV alone, the requisite expression of Rta reveals a previously unappreciated role for Notch in reactivation. We propose that activated Notch cooperates with Rta in a promoter-specific manner that is partially programmed by Rta’s ability to redistribute RBP-Jk DNA binding to the virus during reactivation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus type 1 (HIV-1) gradually destroys the CD4+ T cells leading to immune system dysfunction. HIV-1 can result in acquired immunodeficiency syndrome (AIDS) if antiretroviral drugs are not used. HIV/AIDS patients are more vulnerable to opportunistic infections or cancers. Human herpesvirus 8 (HHV-8) targets B cells and causes an AIDS-related cancer known as kaposi sarcoma (KS). Numerous investigations have demonstrated co-infection instances between HIV-1 and HHV-8. In this research, we investigated the co-dynamics of HIV-1 and HHV-8 in vivo using a system of delay differential equations (DDEs). The model explained the interactions between uninfected CD4+ T cells, latently/actively HIV-1-infected CD4+ T cells, free HIV1 particles, uninfected B cells, latently/actively HHV-8-infected B cells, and free HHV-8 particles. Eight distributed-time delays were incorporated into the model to account for the delays that arose during the generation of both actively and latently infected cells, the activation of latent reservoirs, and the maturation of freshly discharged virions. By examining the nonnegativity and boundedness of the solutions, we demonstrated that the model was both mathematically and biologically well-posed. We calculated the model’s equilibria and threshold numbers. We studied the global asymptotic stability of the model’s equilibria by building appropriate Lyapunov functionals and applying the Lyapunov-LaSalle asymptotic stability theorem. Numerical simulations were used to display the results. For the basic reproduction numbers of HHV-8 single-infection (R1) and HIV-1 single-infection (R2), sensitivity analysis was carried out. Comparing HIV-1 or HHV-8 single infections with co-infections of HHV-8 and HIV-1 was shown. It’s interesting to note that we detected larger amounts of HHV-8 and HIV-1 when they co-infect than when they are infected alone. This outcome aligned with several findings seen in the literature. The effect of antiviral drugs and time delays on the co-dynamics of HIV-1 and HHV-8 was investigated. We found that the delay parameter and drug effectiveness both contributed to a decrease in the basic reproduction numbers, R1 and R2. Less treatment efficacies will be needed to keep the system at the infection-free equilibrium and remove HIV-1 and HHV-8 from the body if a model with time delays is employed. [ABSTRACT FROM AUTHOR]

Kaposi’s sarcoma-associated herpesvirus (KSHV) belongs to the gamma-herpesvirus family and is a well-known human oncogenic virus. In infected cells, the viral genome of 165 kbp is circular DNA wrapped in chromatin. The tight control of gene expression is critical for latency, the transition into the lytic phase, and the development of viral-associated malignancies. Distal cis-regulatory elements, such as enhancers and silencers, can regulate gene expression in a position- and orientation-independent manner. Open chromatin is another characteristic feature of enhancers. To systematically search for enhancers, we cloned all the open chromatin regions in the KSHV genome downstream of the luciferase gene and tested their enhancer activity in infected and uninfected cells. A silencer was detected upstream of the latency-associated nuclear antigen promoter. Two constitutive enhancers were identified in the K12p-OriLyt-R and ORF29 Intron regions, where ORF29 Intron is a tissue-specific enhancer. The following promoters: OriLyt-L, PANp, ALTp, and the terminal repeats (TRs) acted as lytically induced enhancers. The expression of the replication and transcription activator (RTA), the master regulator of the lytic cycle, was sufficient to induce the activity of lytic enhancers in uninfected cells. We propose that the TRs that span about 24 kbp region serve as a “viral super-enhancer” that integrates the repressive effect of the latency-associated nuclear antigen (LANA) with the activating effect of RTA. Utilizing CRISPR activation and interference techniques, we determined the connections between these enhancers and their regulated genes. The silencer and enhancers described here provide an additional layer to the complex gene regulation of herpesviruses. IMPORTANCE In this study, we performed a systematic functional assay to identify cis-regulatory elements within the genome of the oncogenic herpesvirus, Kaposi’s sarcoma-associated herpesvirus (KSHV). Similar to other herpesviruses, KSHV presents both latent and lytic phases. Therefore, our assays were performed in uninfected cells, during latent infection, and under lytic conditions. We identified two constitutive enhancers, one of which seems to be a tissue-specific enhancer. In addition, four lytically induced enhancers, which are all responsive to the replication and transcription activator (RTA), were identified. Furthermore, a silencer was identified between the major latency promoter and the lytic gene locus. Utilizing CRISPR activation and interference techniques, we determined the connections between these enhancers and their regulated genes. The terminal repeats, spanning a region of about 24 kbp, seem like a “viral super-enhancer” that integrates the repressive effect of the latency-associated nuclear antigen (LANA) with the activating effect of RTA to regulate latency to lytic transition. [ABSTRACT FROM AUTHOR]

ABSTRACT Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic virus involved in several diseases. The gold standard for KSHV sero diagnosis remains the indirect immunofluorescence assay (IFA), which is time-consuming and operator-dependent. We compared this method with an enzyme-linked immunosorbent assay (ELISA) targeting solubilized KSHV whole-genome extract among positive (n = 49, including 76% of HIV-infected patients) and negative (n = 14) control groups. We also included 14 sera with equivocal IFA results. ELISA showed better performance in detecting KSHV antibodies (McNemar’s test, P = 0.0455). The sensitivity and specificity of both methods were 79% (64–89) and 100% (66–100) for the IFA, respectively, and 94% (83–99) and 100% (66–100) for ELISA, respectively. All IFA equivocal results were either negative or positive with ELISA. ELISA is more reliable and could be a good alternative for determining KSHV serological status, particularly in the context of immunocompromised patients and equivocal serology with the IFA.IMPORTANCEKaposi’s sarcoma-associated herpesvirus (KSHV) sero status remains challenging because no perfect reference is available for the detection of KSHV antibodies. The current gold-standard method, the indirect immunofluorescence assay (IFA), has a very good specificity of close to 100%, but a lower sensitivity of around 80–85%, which decreases to 64–67% in immunocompromised patients. Additionally, this method is time-consuming and operator-dependent compared with new serological assays such as the enzyme-linked immunosorbent assay (ELISA). Thus, further research is still needed to improve KSHV sero diagnosis. Here, we compare the KSHV IgG ELISA kit assay (Advanced Biotechnologies Inc) with the gold-standard IFA, targeting the LANA-1 protein from latent BC-3 cell lines.

Background: Multicentric Castleman disease (MCD) is a rare, aggressive lymphoproliferative disorder. Human herpesvirus-8 (HHV-8) has an important role in the pathogenesis of the disease and its association with Kaposi’s sarcoma has been reported, especially in people living with human immunodeficiency virus (HIV). In this report, we present the case of HHV-8 positive MCD accompanied by Kaposi’s sarcoma and multiple myeloma in an HIV-negative patient. Case Report: A 78-year-old man with Kaposi’s sarcoma presented with B symptoms, pancytopenia, lymphadenopathy, and splenomegaly. The bone marrow biopsy demonstrated 70% lambda-restricted monotypic plasma cell infiltration consistent with plasma dyscrasia. Also, the patient was diagnosed with HHV-8 positive MCD as a result of inguinal lymph node excisional biopsy. Treatment was initiated including ganciclovir and methylprednisolone and followed by rituximab. The patient passed away at the 24th hour of rituximab infusion due to shock. Conclusions: MCD and associated malignancies are difficult to treat and have a poor prognosis. More studies and data are needed to manage these patients.

Acquired immunodeficiency syndrome (AIDS)-associated Kaposi sarcoma (KS) is an angioproliferative neoplasia caused by infection with human herpesvirus 8 (HHV-8). It typically presents with mucocutaneous involvement, but it can be disseminated. Initial presentation with primarily pulmonary KS is rare. We present a case of a 32-year-old male with untreated human immunodeficiency virus (HIV) diagnosed 1 year before presentation who developed progressively worsening cough and shortness of breath for 6 months. He was hospitalized twice and treated for unresolved pneumonia in an outside hospital. The patient concomitantly developed purplish nodules on his face, then the upper trunk, back, chest, and thighs bilaterally that gradually increased in size and number. Histopathology findings from skin lesions were consistent for KS. Bronchoscopy found multiple erythematous plaques throughout the tracheobronchial tree with telangiectasias and inflammation suggestive of pulmonary KS. His imaging findings and positive serum HHV-8 polymerase chain reaction (PCR) were consistent with disseminated KS. He started antiretroviral therapy (ART) to treat his HIV infection, followed by liposomal doxorubicin chemotherapy. But both ART and chemotherapy were interrupted due to adherence and insurance issues. The patient was readmitted with acute respiratory failure requiring mechanical ventilation with multiple vasopressors that led to the patients demise. The late recognition of KS diagnosis and delayed treatment can lead to worse outcomes.

Introduction: Lupus is a chronic systemic disorder with a complex etiology, and viral infections have contributed to its development and progression. Human herpesvirus-8 (HHV-8) has been diagnosed in many patients with autoimmune disorders; however, its role in lupus has not been well investigated. The present study aimed to compare the frequency and viral load of HHV-8 in patients with lupus and healthy population. Material & Methods: In this cross-sectional study, 70 patients with lupus and 70 healthy individuals who were matched for gender and age were included. After the extraction of viral DNA, the HHV-8 viral load was measured using the Real-time polymerase chain reaction (PCR) technique, and the results were analyzed by SPSS software. Results: Patients with lupus consisted of 59 females (84.3%) and 11 males (15.7%) with a mean age of 31.1±8.4 years, and the control group consisted of 58 females (82.9%) and 12 males (17.1%) with a mean age of 33.5±11.2 years, none of them were positive for HHV-8 genome. Discussion & Conclusion: To date, there is no report in this field from Iran, and this study is the first survey. Regarding the high accuracy of the Real-time PCR technique and lack of HHV-8 genome in the blood samples of Iranian patients with lupus, it seems that none of the individuals, even in the case of viral infection, were infected with the active form of HHV-8, which is compatible with the previous studies.

Kaposi sarcoma (KS) arises in the context of 4 epidemiologic-clinical settings: Classic, endemic, epidemic, and iatrogenic; the most serious types are endemic and epidemic, and visceral involvement occurs mostly in the latter. Several morphological variants of KS have been described, of which the anaplastic one is highly aggressive. We report the case of an anaplastic KS arising from the ascending colon in a 32-year-old human immunodeficiency virus (HIV)-positive male patient with a 6-year history of multiple mucocutaneous KS. Anaplastic KS is most frequent in endemic and classic settings; there are ten cases of anaplastic KS reported in HIV-positive male patients. There is now strong evidence that KS is a clonal neoplasm characterized by chromosomal instability at the molecular level. According to the morphological spectrum and contemporary hypotheses of oncogenesis, conventional KS should be considered an incipient endothelial neoplasia, multiple or single, and anaplastic KS, the fully developed stage of the malignant neoplasm. [ABSTRACT FROM AUTHOR]

Human Herpesvirus 8 (HHV‐8) has been classified by sequence analysis of open reading frame (ORF) K1, ORF K15, and variable sequence loci within the central constant region. The purpose of this study was to examine the molecular epidemiology of HHV‐8 in an Irish population. This retrospective study included 30 patients who had HHV‐8 DNA detected in plasma. Nested end‐point PCR was used to characterise four regions of the HHV‐8 genome, K1, T0.7 (K12), ORF 75, and K15. Sequencing data were obtained for 23 specimens from 19 patients. Phylogenetic analysis of ORF K1 demonstrated that subtypes A, B, C and F were present in 37%, 11%, 47% and 5%, respectively. For T0.7 and ORF 75, sequencing data were obtained for 12 patients. For T0.7, subtypes A/C, J, B, R and Q were present in 58%, 17%, 8%, 8%, and 8%, respectively. For ORF 75, subtypes A, B, C and D were present in 58%, 8%, 25%, and 8%, respectively. K15 sequences were determined for 13 patients. 69% had the P allele and 31% had the M allele. The data generated by this study demonstrate that a broad variety of HHV‐8 subtypes are represented in patients exhibiting HHV‐8‐related disease in Ireland, a low prevalence country. The predominance of C and A K1 subtypes was as expected for a Western European population. The 31% prevalence for K15 subtype M was higher than expected for a Western European population. This may represent the changing and evolving epidemiology in Ireland due to altered migration patterns. [ABSTRACT FROM AUTHOR]

Introduction: Lupus is a chronic systemic disorder with a complex etiology, and viral infections have contributed to its development and progression. Human herpesvirus-8 (HHV-8) has been diagnosed in many patients with autoimmune disorders; however, its role in lupus has not been well investigated. The present study aimed to compare the frequency and viral load of HHV-8 in patients with lupus and healthy population. Material & Methods: In this cross-sectional study, 70 patients with lupus and 70 healthy individuals who were matched for gender and age were included. After the extraction of viral DNA, the HHV-8 viral load was measured using the Real-time polymerase chain reaction (PCR) technique, and the results were analyzed by SPSS software. Results: Patients with lupus consisted of 59 females (84.3%) and 11 males (15.7%) with a mean age of 31.1±8.4 years, and the control group consisted of 58 females (82.9%) and 12 males (17.1%) with a mean age of 33.5±11.2 years, none of them were positive for HHV-8 genome. Discussion & Conclusion: To date, there is no report in this field from Iran, and this study is the first survey. Regarding the high accuracy of the Real-time PCR technique and lack of HHV-8 genome in the blood samples of Iranian patients with lupus, it seems that none of the individuals, even in the case of viral infection, were infected with the active form of HHV-8, which is compatible with the previous studies. [ABSTRACT FROM AUTHOR]

Objective: Kaposi’s sarcoma (KS) is a vascular proliferation associated with Human Herpes Virus 8. Typical histopathological findings of KS are characterized by vascular proliferation, inflammatory cell infiltration, extravasated erythrocytes and spindle cell proliferation, although it varies according to the stage. In this study, the clinical-histopathological features of patients with KS were examined. The value of histopathological parameters in the diagnosis was investigated. Methods: Patients with KS diagnosed in University of Health Sciences Turkey, Samsun Training and Research Hospital Medical Pathology Department between 2016-2020 were retrospectively scanned. Clinical and tumor features and histopathological changes in the surrounding tissue were evaluated. Results: The most common histopathological features belonging to tumor were extravasated erythrocytes, spindle cell changes, fascicle formation, slit-like space; the most common epidermal features were hyperkeratosis and acanthosis; the most common peritumoral features were the presence of large vessels and ectatic vessels in the periphery. There was a significant relationship between the promontory sign and the lymphangioma-like area and ulcer. Also there was a significant relationship between nuclear atypia and lymphangioma-like area. Conclusion: While most of the histopathological features are characteristic for KS, none of them alone is specific. They should be evaluated together with all structural, tumoral and peritumoral features during the diagnostic approach.

Patients with acquired immunodeficiency syndrome (AIDS) are at an increased susceptibility to pathogens and associated malignancies which can present with a unique constellation of symptoms. In this article, we describe a case of Castleman disease in a patient with AIDS, nonadherent with antiretroviral therapy (ART), who presented with fevers, constant abdominal pain, nausea, and vomiting. After an extensive work up, a lymph node biopsy confirmed a diagnosis of human herpesvirus-8 (HHV-8)-associated multicentric Castleman disease. Patients presenting with AIDS and fever have broad differential diagnoses; therefore, reaching a diagnosis as rare as Castleman disease can be challenging. HHV-8 has a propensity to CD20 positive B cells, which allows rituximab to be an effect treatment.

Kaposi's sarcoma (KS) is an AIDS-defining illness caused by Kaposi's sarcoma-associated herpesvirus (KSHV) predominantly in the context of HIV-related immune suppression. We aimed to explore the usefulness of KSHV DNA viral load (VL) measurement in predicting the severity, response to treatment and outcome of KS. We retrospectively assessed a cohort of KS patients (n = 94) receiving treatment at Groote Schuur Hospital, Cape Town, South Africa. Demographic and clinical data, KS staging and response to treatment were extracted from patient files, while long-term survival was ascertained from hospital records. KSHV serology and VL and hIL-6 were determined empirically from patients' blood. All patients were HIV-positive adults, the majority of whom were on HAART at the time of recruitment. KSHV VL was detectable in 65 patients' blood (median: 280.5/106 cells (IQR: 69.7–1727.3)) and was highest in patients with S1 HIV-related systemic disease (median 1066.9/106 cells, IQR: 70.5–11,269.6). KSHV VL was associated with the S1 stage in a binomial regression controlling for confounders (adjusted odds ratio 5.55, 95% CI: 1.28–24.14, p = 0.022). A subset of six patients identified to have extremely high KSHV VLs was predominantly T1 stage with pulmonary KS, and most had died at follow-up. In our cohort, elevated KSHV VL is associated with systemic HIV-related illness in KS disease. Extremely high KSHV VLs warrant further investigation for patients potentially requiring intensive treatment and investigation for progression or diagnosis of concurrent KSHV lytic syndromes. [ABSTRACT FROM AUTHOR]

Kaposi sarcoma (KS), caused by Herpesvirus‐8 (HHV‐8; KSHV), shows sporadic, endemic, and epidemic forms. While familial clustering of KS was previously recorded, the molecular basis of hereditary predilection to KS remains largely unknown. We demonstrate through genetic studies that a dominantly inherited missense mutation in BPTF segregates with a phenotype of classical KS in multiple immunocompetent individuals in two families. Using an rKSHV.219‐infected CRISPR/cas9‐model, we show that BPTFI2012T mutant cells exhibit higher latent‐to‐lytic ratio, decreased virion production, increased LANA staining, and latent phenotype in viral transcriptomics. RNA‐sequencing demonstrated that KSHV infection dysregulated oncogenic‐like response and P53 pathways, MAPK cascade, and blood vessel development pathways, consistent with KS. BPTFI2012T also enriched pathways of viral genome regulation and replication, immune response, and chemotaxis, including downregulation of IFI16, SHFL HLAs, TGFB1, and HSPA5, all previously associated with KSHV infection and tumorigenesis. Many of the differentially expressed genes are regulated by Rel‐NF‐κB, which regulates immune processes, cell survival, and proliferation and is pivotal to oncogenesis. We thus demonstrate BPTF mutation‐mediated monogenic hereditary predilection of KSHV virus‐induced oncogenesis, and suggest BPTF as a drug target. [ABSTRACT FROM AUTHOR]

Copyright of Bezmialem Science is the property of Galenos Yayinevi Tic. LTD. STI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

This qualitative sub-study investigated household practices affecting orally shed infections using Kaposi's sarcoma-associated herpesvirus (KSHV) as a focus. Participants enrolled from 50 households in rural south-western Uganda were followed monthly up to three times. At enrolment, in-depth interviews were completed, and venous blood collected. KSHV seropositivity was defined as anti-KSHV antibody detection to any of 25 antigens by multiplex bead-based assay. Mouthwash samples from every visit were tested by qPCR and KSHV shedders defined as individuals with KSHV DNA detected. At least one KSHV seropositive person was in 48/49(98%) households. Among those, 79% had 1+ KSHV shedders including 45% with 1+ always shedders and 92% with 1+ intermittent shedders, not mutually exclusively. All respondents reported feeding infants with pre-masticated hard food/fruits and testing food/tea temperature. Temperature was tested by tasting, pouring tea on their hand, or touching the cup to their cheek. Some cooled food/tea using a utensil or blowing over it. Food sharing amongst children and adults and using the same dish was common practice. To treat colic pain, carers/mothers reported chewing herbs and spitting into the child's mouth. Feeding and treatment practices did not vary by KSHV status. We identified potential KSHV transmission modes in rural Ugandan households. [ABSTRACT FROM AUTHOR]

Human herpesvirus‐8 (HHV‐8) viremia is associated with refractory conditions in patients infected with HIV‐1. Therefore, we evaluated the factors related to plasma HHV‐8‐DNA. Participants included patients infected with HIV‐1 who visited our hospital. Plasma HHV‐8‐DNA levels were measured using real‐time polymerase chain reaction, and anti‐HHV‐8 antibodies were assessed through enzyme immunoassays using multiple antigens (K8.1, ORF59, ORF65, and LANA). Factors related to plasma HHV‐8‐DNA were examined using Fisher's exact test or Mann–Whitney U test. The study involved 36 patients infected with HIV‐1, of whom 19 were histologically diagnosed with Kaposi's sarcoma (KS), two had multicentric Castleman's disease (MCD), and 15 did not exhibit HHV‐8‐related disease. Before the introduction of antiretroviral therapy (ART), plasma HHV‐8‐DNA was detected in 44% (7/16) of patients with KS and in 9% (1/11) of patients without HHV‐8‐related disease. Among patients with KS, elevated plasma HHV‐8‐DNA levels (≥0.05 copies/µL) correlated with the presence of CDC category C diseases other than KS (p = 0.0337), anti‐HHV‐8 antibody negativity (p = 0.0337), anemia (p = 0.0474), and thrombocytopenia (p = 0.0146). Following ART initiation, the percentage of patients positive for plasma HHV‐8‐DNA decreased from 44% (7/16) to 6% (1/17), and the percentage of patients positive for anti‐HHV‐8 antibodies increased from 44% (7/16) to 88% (15/17). Finally, plasma HHV‐8‐DNA positivity and anti‐HHV‐8 antibody negativity were observed in two patients with MCD. Our findings suggest that insufficient production of anti‐HHV‐8 antibodies was associated with HHV‐8 viremia, and that anti‐HHV‐8 antibody production was recovered with ART; thus, indicating the possibility of involvement of humoral immunity in suppressing HHV‐8 viremia. [ABSTRACT FROM AUTHOR]

Kaposi's sarcoma should be considered in the differential diagnosis in young patients with penile lesions and no risk factors. A 37-year-old heterosexual man with no other medical history applied presented with a non-itchy and painless penile lesion, for three months. The HIV 1-2 serology was negative via ELISA test. Histopathological analysis of the lesion revealed a tumor composed of atypical spindle cells, below a partially ulcerated surface. There was also an abundance of plasma cells admixed within the neoplastic cells. The patient was diagnosed as HIV-negative, HHV-8 positive Kaposi sarcoma. Although penile Kaposi sarcoma is extremely rare, classical Kaposi sarcoma should be considered in the differential diagnosis of penile lesions. [ABSTRACT FROM AUTHOR]

Acquired immunodeficiency syndrome (AIDS)-associated Kaposi sarcoma (KS) is an angioproliferative neoplasia caused by infection with human herpesvirus 8 (HHV-8). It typically presents with mucocutaneous involvement, but it can be disseminated. Initial presentation with primarily pulmonary KS is rare. We present a case of a 32-year-old male with untreated human immunodeficiency virus (HIV) diagnosed 1 year before presentation who developed progressively worsening cough and shortness of breath for 6 months. He was hospitalized twice and treated for unresolved pneumonia in an outside hospital. The patient concomitantly developed purplish nodules on his face, then the upper trunk, back, chest, and thighs bilaterally that gradually increased in size and number. Histopathology findings from skin lesions were consistent for KS. Bronchoscopy found multiple erythematous plaques throughout the tracheobronchial tree with telangiectasias and inflammation suggestive of pulmonary KS. His imaging findings and positive serum HHV-8 polymerase chain reaction (PCR) were consistent with disseminated KS. He started antiretroviral therapy (ART) to treat his HIV infection, followed by liposomal doxorubicin chemotherapy. But both ART and chemotherapy were interrupted due to adherence and insurance issues. The patient was readmitted with acute respiratory failure requiring mechanical ventilation with multiple vasopressors that led to the patient's demise. The late recognition of KS diagnosis and delayed treatment can lead to worse outcomes. [ABSTRACT FROM AUTHOR]

Molecular interactions between viral DNA and viral-encoded protein are a prerequisite for successful herpesvirus replication and production of new infectious virions. Here, we examined how the essential Kaposi’s sarcoma-associated herpesvirus (KSHV) protein, RTA (replication and transcription activator), binds to viral DNA using transmission electron microscopy (TEM). Previous studies using gel-based approaches to characterize RTA binding are important for studying the predominant form(s) of RTA within a population and identifying the DNA sequences that RTA binds with high affinity. However, using TEM, we were able to examine individual protein-DNA complexes and capture the various oligomeric states of RTA when bound to DNA. Hundreds of images of individual DNA and protein molecules were collected and then quantified to map the DNA-binding positions of RTA bound to the two KSHV lytic origins of replication encoded within the KSHV genome. The relative size of RTA or RTA bound to DNA was then compared to protein standards to determine whether RTA complexed with DNA was monomeric, dimeric, or formed larger oligomeric structures. We successfully analyzed a highly heterogeneous data set and identified new DNA-binding sites for RTA that included both high- and low-frequency-binding sites. TEM micrographs provide evidence that the majority of RTA analyzed forms dimers and high order multimers when bound to KSHV origin of replication DNA sequences. Broadly, our findings expand upon our understanding of the degree to which DNA-binding locations and protein conformation are heterogeneous and how protein monomers and dimers function differently with respect to DNA-binding location specificity. Kaposi’s sarcoma-associated herpesvirus (KSHV) is a human herpesvirus associated with several human cancers, typically in patients with compromised immune systems. Herpesviruses establish lifelong infections in hosts in part due to the two phases of infection: the dormant and active phases. Effective antiviral treatments to prevent the production of new viruses are needed to treat KSHV. A detailed microscopy-based investigation of the molecular interactions between viral protein and viral DNA revealed how protein-protein interactions play a role in DNA-binding specificity. This analysis will lead to a more in-depth understanding of KSHV DNA replication and serve as the basis for anti-viral therapies that disrupt and prevent the protein-DNA interactions, thereby decreasing spread to new hosts. [ABSTRACT FROM AUTHOR]

In this study, we investigated the integration of Human Herpesvirus 8 (HHV-8) into the human genome using the primary effusion lymphoma (PEL) cell line BC-3. Through next-generation sequencing (NGS) data from multiple independent sequencing runs, we identified two highly supported HHV-8 integrants. These integrants encompassed a region of human chromosome 12 that was amplified approximately 16-fold between the junctions. Significantly, these events could represent the first known instance of HHV-8 integration into a hybrid human-viral extrachromosomal chimeric circular DNA (eccDNA). The amplified fragment contained partial or complete copies of various human genes, including SELPLG and CORO1C. Analysis of long-read Nanopore data indicated that the CpGs at the SELPLG promoter were mostly unmethylated, suggesting that the additional copies of SELPLG within this eccDNA are likely transcriptionally active. Our findings suggest that viral insertion and eccDNA amplification could be crucial mechanisms in the development of HHV-8-related cancers. In conclusion, our study provides valuable insights into the molecular mechanisms involved in HHV-8-induced oncogenesis and emphasizes the importance of investigating viral integration and eccDNAs in cancer development. Furthermore, we highlight the necessity of employing multiple independent sequencing approaches to validate integration events and avoid false positives derived from library construction artifacts. [ABSTRACT FROM AUTHOR]

Background: Human herpesvirus 8 (HHV-8) stimulates lymphoproliferation, by activating the signaling pathway of the interleukin-6 receptor, along with several other regulatory mechanisms. The presence of specific genetic variations governing immune responses can impact the promotion or suppression of malignant lymphoma. Polymorphisms in the gene cluster of interleukin-1 (IL-1) have been identified as significant contributors to the regulation of inflammation. Objective: This study aimed to determine the percentage HHV-8 and whether polymorphisms at IL-1 receptor antagonist (IL-1ra) locus modulate the risk of developing malignant lymphoma of a group of Iraqi patients in the Mid-Euphrates Sector, Iraq. Materials and Methods: A case-control study was conducted on 200 specimens obtained from patients with lymphoma and individuals without any apparent health conditions who served as the control group (considered normal individuals). The specimens were collected from various general hospitals and private clinics located in the Middle Euphrates region of Iraq. The study population included individuals aged between 17 and 75 years. Specimen collection took place between October 2022 and February 2023. Conventional polymerase chain reaction (PCR) was chosen for the detection of HHV-8 as well as IL-1ra gene polymorphism by sequencing. Results: According to PCR detection, 31 out of 64 (48.4%) of the specimens revealed PCR detection positivity for HHV-8, whereas 33 out of 64 (51.6%) specimens showed negative detection for HHV-8. The lymphoma which were most HHV-8-infected are related to the age stratum (56–75 years), accounted for 48%, whereas the age strata 15–35 years, and 36–55 years, each accounted for 23% and 29%, respectively. Conclusion: In view of the relatively small numbers included in our study, the present results indicate the possibility that HHV-8 and IL-1ra polymorphism may play a role in the tumor biology of lymphocyte and may contribute to their development. [ABSTRACT FROM AUTHOR]

Copyright of Yeni Üroloji Dergisi is the property of Ali Ihsan Tasci and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi’s sarcoma (KS) and primary effusion lymphoma (PEL), which preferentially arise in immunocompromised patients while lack of effective therapeutic options. Oncoproteins Myc and hypoxia-inducible factor-1α (HIF1α) have been found closely related to KSHV infection, replication and oncogenesis. However, the strategies of dual targeting these two oncoproteins have never been developed and tested for treatments of KSHV-related malignancies. In the current study, we report that treatment of echinomycin dramatically regresses cell growth both in vitro-cultured KSHV + tumor cells and in vivo KS or PEL xenograft mice models, through simultaneously inhibiting Myc and HIF1α expression. Echinomycin treatment also induces viral lytic gene expression whereas not increasing infectious virions production from KSHV + tumor cells. Our comparative transcriptomic analysis has identified a bunch of new Echinomycin-regulated, Myc- and HIF1α-related genes contributed to KSHV pathogenesis, including KDM4B and Tau, which are required for the survival of KSHV + tumor cells with functional validation. These data together reveal that dual targeting Myc and HIF1α such as using Echinomycin may represent a new and promising option for treatments of these virus-associated malignancies.

Abstract Background The coinfection between cytomegalovirus (CMV) and either human herpesvirus‐6 (HHV‐6) or HHV-7 in renal transplant recipients is well known; however, there have been few reports of coinfection of CMV associated with HHV-8. This paper presents a first case of acute gastric ulcer and duodenitis associated with CMV and HHV‐8 coinfection after renal transplantation. Case presentation A 33-year-old male with a history of kidney transplantation was admitted to hospital because of postural epigastric pain. The recipient was CMV seropositive prior to transplantation and received trimethoprim-sulfamethoxazole without universal prophylaxis. Approximately 5 months after renal transplant, the recipient complained postural epigastric pain. An endoscopy revealed diffuse ulcerative lesions in the lower body and in the antrum of the stomach, as well as several erythematous mucosal lesions in the duodenum. Histopathologic examination identified CMV inclusions consistent with invasive CMV disease and immunohistochemical staining showed positive results for HHV-8 and CMV. No tumorous diseases such as Kaposi’s sarcoma were detected. After 3 weeks of intravenous ganciclovir treatment, we observed that serum CMV PCR remained within the normal range and clinical symptoms improved. A follow-up endoscopy performed 3 weeks later showed that the severity of the above mentioned lesions had improved. Conclusions We report the first case of a renal transplant recipient diagnosed with acute gastric ulcer and duodenitis associated with coinfection of CMV and HHV-8. Ganciclovir appears to be effective in diseases associated with coinfection of CMV and HHV-8.

Abstract Background The spleen is frequently scanned in workup of infections. Hypoechoic splenic micro-abscesses are known signs of disseminated tuberculosis in HIV co-infected patients. The spleen of HIV patients is thus often scanned using high-frequency transducers. Methods and findings We describe a reticulo-nodular “sponge pattern” in the spleen of an HIV-positive patient with Hodgkin’s lymphoma. Disseminated throughout the spleen, very small (1.5–2.0 mm) hypoechoic lesions having a branching reticulo-nodular distribution were seen. The lesions partly, but not entirely, follow splenic vasculature. Review of stored images of other patients identified 15 more cases showing a similar pattern. All patients were HIV positive, almost all with CD4 counts below 200 cells/mm3. Seven (44%) were additionally diagnosed with HHV-8-associated diseases, but the pattern was seen with various underlying opportunistic infections. Discussion and conclusion After comparison with spleen microscopic anatomy, we hypothesize that the white pulp of spleens in our patients is hyperplastic or otherwise changed in consistency to be better visible by high-frequency ultrasound. Concomitant human herpesvirus-8 infection may be another cause of this visible white pulp. While we can only speculate about the etiology of the splenic “sponge pattern,” it needs to be recognized as it may be misinterpreted as splenic micro-abscesses of disseminated infections, like tuberculosis in severely immune-compromised patients.

Background: Human herpesvirus 8 (HHV-8) stimulates lymphoproliferation, by activating the signaling pathway of the interleukin-6 receptor, along with several other regulatory mechanisms. The presence of specific genetic variations governing immune responses can impact the promotion or suppression of malignant lymphoma. Polymorphisms in the gene cluster of interleukin-1 (IL-1) have been identified as significant contributors to the regulation of inflammation. Objective: This study aimed to determine the percentage HHV-8 and whether polymorphisms at IL-1 receptor antagonist (IL-1ra) locus modulate the risk of developing malignant lymphoma of a group of Iraqi patients in the Mid-Euphrates Sector, Iraq. Materials and Methods: A case-control study was conducted on 200 specimens obtained from patients with lymphoma and individuals without any apparent health conditions who served as the control group (considered normal individuals). The specimens were collected from various general hospitals and private clinics located in the Middle Euphrates region of Iraq. The study population included individuals aged between 17 and 75 years. Specimen collection took place between October 2022 and February 2023. Conventional polymerase chain reaction (PCR) was chosen for the detection of HHV-8 as well as IL-1ra gene polymorphism by sequencing. Results: According to PCR detection, 31 out of 64 (48.4%) of the specimens revealed PCR detection positivity for HHV-8, whereas 33 out of 64 (51.6%) specimens showed negative detection for HHV-8. The lymphoma which were most HHV-8-infected are related to the age stratum (56–75 years), accounted for 48%, whereas the age strata 15–35 years, and 36–55 years, each accounted for 23% and 29%, respectively. Conclusion: In view of the relatively small numbers included in our study, the present results indicate the possibility that HHV-8 and IL-1ra polymorphism may play a role in the tumor biology of lymphocyte and may contribute to their development.

In this study, we investigated the integration of Human Herpesvirus 8 (HHV-8) into the human genome using the primary effusion lymphoma (PEL) cell line BC-3. Through next-generation sequencing (NGS) data from multiple independent sequencing runs, we identified two highly supported HHV-8 integrants. These integrants encompassed a region of human chromosome 12 that was amplified approximately 16-fold between the junctions. Significantly, these events could represent the first known instance of HHV-8 integration into a hybrid human-viral extrachromosomal chimeric circular DNA (eccDNA). The amplified fragment contained partial or complete copies of various human genes, including SELPLG and CORO1C. Analysis of long-read Nanopore data indicated that the CpGs at the SELPLG promoter were mostly unmethylated, suggesting that the additional copies of SELPLG within this eccDNA are likely transcriptionally active. Our findings suggest that viral insertion and eccDNA amplification could be crucial mechanisms in the development of HHV-8-related cancers. In conclusion, our study provides valuable insights into the molecular mechanisms involved in HHV-8-induced oncogenesis and emphasizes the importance of investigating viral integration and eccDNAs in cancer development. Furthermore, we highlight the necessity of employing multiple independent sequencing approaches to validate integration events and avoid false positives derived from library construction artifacts.

Human herpesvirus type 8 (HHV‐8) unrelated primary effusion lymphoma (PEL) like lymphoma (PEL‐LL) is an exceedingly rare non‐Hodgkin lymphoma with no characteristic symptoms and consensus on the optimal treatment. This case report presents a 55‐year‐old man with prior HBV‐related Child‐Pugh B liver cirrhosis and developing activity‐related dyspnea. A moderate amount of pleural effusion was identified without tumor masses, and cytological studies confirmed a diagnosis of PEL‐LL. The patient received rituximab and lenalidomide, albeit with HBV infection, and is currently on maintenance therapy with resolving symptoms but without HBV reactivation. Hence, the R2 protocol (rituximab and lenalidomide) might be clinically effective and safe for PEL‐LL patients with HBV infection and Child‐Pugh B liver cirrhosis. [ABSTRACT FROM AUTHOR]

Abstract Background There have hardly been any reported cases of children presenting with Kaposi sarcoma as a second malignancy following treatment for acute lymphoblastic leukemia outside a transplant setting. Case presentation We report a case of a 5-year-old boy of Bantu origin, which, to our knowledge, could be only the second reported case of oral–visceral Kaposi sarcoma after acute lymphoblastic leukemia treatment. The patient presented with a 1-month history of progressive, non-painful, soft tissue oral mass, 1 month after completing treatment for high-risk acute lymphoblastic leukemia. He was successfully treated for Kaposi sarcoma on a two-drug regimen (bleomycin and vincristine) with good clinical response. Conclusion Visceral Kaposi sarcoma as a second malignancy may occur after pediatric acute lymphoblastic leukemia treatment, but its rarity makes it unlikely to raise suspicion among clinicians, thus precluding early diagnosis and treatment. We recommend routine evaluation for Kaposi sarcoma lesions in children undergoing long-term surveillance following treatment for childhood acute leukemia.

Abstract Background Pericardial effusion is a late manifestation of HIV more commonly observed in individuals with depressed CD4 counts. Although Mycobacterium tuberculosis remains to be one of the most frequently identified pathogens in the pericardial fluid among people living with HIV, less commonly described etiologies include SARS-CoV-2 that causes coronavirus disease and human herpesvirus-8 which is associated with Kaposi sarcoma. Isolation of more than one pathogen in normally sterile sites remains challenging and rare. We report the first documentation of both SARS-CoV-2 and HHV-8 in the pericardial fluid. Case presentation We present the case of a young man in his 20s with a recent history of clinically diagnosed pulmonary tuberculosis who was admitted for progressive dyspnea and cough. He had multiple violaceous cutaneous lesions on the face, neck, and trunk and diffused lymphadenopathies. He tested positive for SARS-CoV-2 on admission. The patient was clinically diagnosed with pneumonia, Kaposi sarcoma, and HIV/AIDS. Empiric broad spectrum antimicrobial regimen was subsequently initiated. HIV with low CD4 count was confirmed during hospitalization. Echocardiography revealed a large pericardial effusion, in impending cardiac tamponade. Frond-like fibrin strands, extending to the parietal pericardium, were also observed. Pericardiostomy yielded hemorrhagic, exudative effusion with lymphocytic predominance. SARS-CoV-2 and HHV-8 were detected in the pericardial fluid, and bacterial, fungal, and tuberculous studies were negative. The patient had clinical improvement after pericardial drainage. However, despite our best clinical care, he developed a nosocomial infection leading to clinical deterioration and death. Conclusion Detection of SARS-CoV-2 and HHV-8 in the pericardial fluid is rare, and interpretation of their significance in clinical care is challenging. However, coronavirus disease and Kaposi sarcoma must be considered and adequately addressed in immunocompromised adults presenting with large pericardial effusion.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL), which preferentially arise in immunocompromised patients while lack of effective therapeutic options. Oncoproteins Myc and hypoxia-inducible factor-1α (HIF1α) have been found closely related to KSHV infection, replication and oncogenesis. However, the strategies of dual targeting these two oncoproteins have never been developed and tested for treatments of KSHV-related malignancies. In the current study, we report that treatment of echinomycin dramatically regresses cell growth both in vitro-cultured KSHV + tumor cells and in vivo KS or PEL xenograft mice models, through simultaneously inhibiting Myc and HIF1α expression. Echinomycin treatment also induces viral lytic gene expression whereas not increasing infectious virions production from KSHV + tumor cells. Our comparative transcriptomic analysis has identified a bunch of new Echinomycin-regulated, Myc- and HIF1α-related genes contributed to KSHV pathogenesis, including KDM4B and Tau, which are required for the survival of KSHV + tumor cells with functional validation. These data together reveal that dual targeting Myc and HIF1α such as using Echinomycin may represent a new and promising option for treatments of these virus-associated malignancies. [ABSTRACT FROM AUTHOR]

Background: Kaposi's sarcoma (KS) is a multifocal, angioproliferative malignant lesion originating from lymphatic endothelial cells. KS limited to the penis is extremely rare in human immunodeficiency virus (HIV) sero-negative patients. In this study, we aimed to present a case of isolated primary penile KS unrelated to HIV. Case Presentation: A 65-year-old man, with no risk factors for KS, presented with reddish nodules on penis. Biopsy was recommended to the patient for definitive diagnosis. Histopathological examination revealed that the diagnosis was classical type KS. No distant metastases were detected. No recurrence or disease progression was detected during the 4-year follow-up. Conclusion: Isolated primary penile KS is extremely rare in HIV sero-negative patients, but it should be kept in mind in the differential diagnosis of pigmented and nodular lesions in the penis. Excision of lesions with negative surgical margins has a high success and very low complication rate, as in our case. [ABSTRACT FROM AUTHOR]

Background: The coinfection between cytomegalovirus (CMV) and either human herpesvirus‐6 (HHV‐6) or HHV-7 in renal transplant recipients is well known; however, there have been few reports of coinfection of CMV associated with HHV-8. This paper presents a first case of acute gastric ulcer and duodenitis associated with CMV and HHV‐8 coinfection after renal transplantation. Case presentation: A 33-year-old male with a history of kidney transplantation was admitted to hospital because of postural epigastric pain. The recipient was CMV seropositive prior to transplantation and received trimethoprim-sulfamethoxazole without universal prophylaxis. Approximately 5 months after renal transplant, the recipient complained postural epigastric pain. An endoscopy revealed diffuse ulcerative lesions in the lower body and in the antrum of the stomach, as well as several erythematous mucosal lesions in the duodenum. Histopathologic examination identified CMV inclusions consistent with invasive CMV disease and immunohistochemical staining showed positive results for HHV-8 and CMV. No tumorous diseases such as Kaposi's sarcoma were detected. After 3 weeks of intravenous ganciclovir treatment, we observed that serum CMV PCR remained within the normal range and clinical symptoms improved. A follow-up endoscopy performed 3 weeks later showed that the severity of the above mentioned lesions had improved. Conclusions: We report the first case of a renal transplant recipient diagnosed with acute gastric ulcer and duodenitis associated with coinfection of CMV and HHV-8. Ganciclovir appears to be effective in diseases associated with coinfection of CMV and HHV-8. [ABSTRACT FROM AUTHOR]