Biologically significant interaction of human herpesvirus 8 viral interferon regulatory factor 4 with ubiquitin-specific protease 7.

Human herpesvirus 8 (HHV-8), associated with Kaposi sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman disease, encodes four interferon regulatory factor homologs, vIRFs 1-4, that interact with and inhibit various mediators of host-cell defense against virus infection. A cellular protein targeted by all the vIRFs is ubiquitin-specific protease 7 (USP7); while replication-modulatory and latently infected PEL-cell pro-viability phenotypes of USP7 targeting have been identified for vIRFs 1-3, the significance of the interaction of vIRF-4 with USP7 has remained undetermined. Here we show, through genetic ablation of the vIRF-4-USP7 interaction in infected cells, that vIRF-4 association with USP7 is necessary for optimal expression of vIRF-4 and normal HHV-8 replication. Findings from experiments on transfected and infected cells identified ubiquitination of vIRF-4 via K48-linkage and USP7-binding-associated suppression of vIRF-4 ubiquitination and, in infected cells, increased vIRF-4 expression. Analysis of IFN-I induction and associated signaling as a function of vIRF-4 and its interaction with USP7 identified a role of each in innate-immune suppression. Finally, activation via K63-polyubiquitination of the innate-immune signaling mediator TRAF3 was found to be suppressed by vIRF-4 in a USP7-binding-associated manner in infected cells, but not in transfected cells, likely via binding-regulated expression of vIRF-4. Together, our data identify the first examples of vIRF ubiquitination and a vIRF substrate of USP7, enhanced expression of vIRF-4 via its interaction with USP7, and TRAF3-inhibitory activity of vIRF-4. The findings address, for the first time, the biological significance of the interaction of vIRF-4 with USP7 and reveal a mechanism of vIRF-4-mediated innate-immune evasion and pro-replication activity via TRAF3 regulation. IMPORTANCE: HHV-8 homologs of cellular interferon regulatory factors (IRFs), involved in host-cell defense against virus infection, interact in an inhibitory fashion with IRFs and other mediators of antiviral innate immunity. These interactions are of demonstrated or hypothesized importance for successful primary, productive (lytic), and latent (persistent) infection by HHV-8. While HHV-8 vIRF-4 is known to interact physically with USP7 deubiquitinase, a key regulator of various cellular proteins, the functional and biological significance of the interaction has not been addressed. The present study identifies the interaction as important for HHV-8 productive replication and, indeed, for vIRF-4 expression and reveals a new function of vIRF-4 via inhibition of the activity of TRAF3, a pivotal mediator of host-cell antiviral activity through activation of cellular IRFs and induction of type-I interferons. These findings identify potential targets for the development of novel anti-HHV-8 agents, such as those able to disrupt vIRF-4-USP7 interaction or vIRF-4-stabilizing USP7 activity.

Kaposi sarcoma-associated herpesvirus complement control protein (KCP) and glycoprotein K8.1 are not required for viral infection in vitro or in vivo.

Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8, is the causal agent of Kaposi sarcoma, a cancer that appears as tumors on the skin or mucosal surfaces, as well as primary effusion lymphoma and KSHV-associated multicentric Castleman disease, which are B-cell lymphoproliferative disorders. Effective prophylactic and therapeutic strategies against KSHV infection and its associated diseases are needed. To develop these strategies, it is crucial to identify and target viral glycoproteins involved in KSHV infection of host cells. Multiple KSHV glycoproteins expressed on the viral envelope are thought to play a pivotal role in viral infection, but the infection mechanisms involving these glycoproteins remain largely unknown. We investigated the role of two KSHV envelope glycoproteins, KSHV complement control protein (KCP) and K8.1, in viral infection in various cell types in vitro and in vivo. Using our newly generated anti-KCP antibodies, previously characterized anti-K8.1 antibodies, and recombinant mutant KSHV viruses lacking KCP, K8.1, or both, we demonstrated the presence of KCP and K8.1 on the surface of both virions and KSHV-infected cells. We showed that KSHV lacking KCP and/or K8.1 remained infectious in KSHV-susceptible cell lines, including epithelial, endothelial, and fibroblast, when compared to wild-type recombinant KSHV. We also provide the first evidence that KSHV lacking K8.1 or both KCP and K8.1 can infect human B cells in vivo in a humanized mouse model. Thus, these results suggest that neither KCP nor K8.1 is required for KSHV infection of various host cell types and that these glycoproteins do not determine KSHV cell tropism. IMPORTANCE: Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic human gamma-herpesvirus associated with the endothelial malignancy Kaposi sarcoma and the lymphoproliferative disorders primary effusion lymphoma and multicentric Castleman disease. Determining how KSHV glycoproteins such as complement control protein (KCP) and K8.1 contribute to the establishment, persistence, and transmission of viral infection will be key for developing effective anti-viral vaccines and therapies to prevent and treat KSHV infection and KSHV-associated diseases. Using newly generated anti-KCP antibodies, previously characterized anti-K8.1 antibodies, and recombinant mutant KSHV viruses lacking KCP and/or K8.1, we show that KCP and K8.1 can be found on the surface of both virions and KSHV-infected cells. Furthermore, we show that KSHV lacking KCP and/or K8.1 remains infectious to diverse cell types susceptible to KSHV in vitro and to human B cells in vivo in a humanized mouse model, thus providing evidence that these viral glycoproteins are not required for KSHV infection.

Valganciclovir modulates the tumor necrosis factor axis molecules expression and CD4+ T-cell subsets in disseminated Kaposi Sarcoma patients.

Valganciclovir (VGC) was used in a randomized clinical trial in patients with disseminated Kaposi Sarcoma/human immunodeficiency virus (DKS/HIV) as add-on therapy to evaluate the proinflammatory axis tumor necrosis factor (TNF) and its receptors (TNFRs) in T cells. Two treatment schedules were used: an experimental regime (ER) and a conventional treatment (CT). Mononuclear cells from patients with DKS/HIV were obtained at baseline (W0), 4 (W4), and 12 weeks (W12). Ten DKS/HIV patients received CT (antiretroviral therapy [cART]) and 10 ER (valganciclovir [VGC] initially, plus cART at the fourth week). HIV+ without KS and HIV- patient groups were included as controls. Correlation between T-cell subsets and HHV-8 viral load (VL) and a multivariate linear regression was performed. Data showed that DKS/HIV patients have an increased frequency of CD8+ T cells, which display a high density of CD8 expression. The ER scheme increases naïve and central memory CD4+ T cells at W4 and W12 of follow-up and induces a balanced distribution of activated CD4+ T-cell subsets. Moreover, ER decreases solTNFR2 since W4 and CT decreased the transmembrane forms of TNF axis molecules. Although CT induces a positive correlation between HHV-8 VL and TNFRs, the use of ER positively correlates with TNF and TNFRs levels through follow-up and a moderate correlation with HHV-8 VL and TNF soluble levels. In conclusion, VGC, as an add-on therapy in DKS/HIV patients, gradually modulates the activation of CD4+ T-cell subsets and the TNF/TNFRs axis, suggesting a better regulation of the inflammatory status.

Kaposi's sarcoma-associated herpesvirus infection and its association with all-cause and cardiovascular mortality in the general adults: A prospective cohort study.

To investigate the association between Kaposi's sarcoma-associated herpesvirus (KSHV)/human herpesvirus 8 (HHV8) infection and both all-cause and cardiovascular mortality in a representative cohort of US adults, data from the National Health and Nutrition Examination Survey III (NHANES III; 1988‒1994) were analyzed, including 13,993 participants aged 18‒90 years who underwent KSHV serology evaluations. Mortality outcomes were ascertained through December 2019 using the National Death Index. Cox proportional hazards models were employed to examine the association between KSHV seropositivity and mortality, adjusting for potential confounders such as age, sex, ethnicity, body mass index, and serum TG. Over a median follow-up period of 26.5 years, 5503 deaths were recorded. KSHV seropositivity was associated with an increased hazard of all-cause mortality (Hazard Ratio [HR]: 1.32, 95% Confidence Interval [CI]: 1.03‒1.69) and cardiovascular mortality (HR: 1.58, 95% CI: 1.00‒2.50) after adjusting for age, sex, ethnicity, and body mass index. Notably, the association between KSHV infection and all-cause mortality persisted among women (HR: 1.32, 95% CI: 1.02‒1.72) after adjusting for all confounders, whereas the association with cardiovascular mortality was only statistically significant for men (HR: 1.90, 95% CI: 1.02, 3.53).KSHV infection may represent an independent risk factor for all-cause and cardiovascular mortality among US adults. These findings highlight the need for further research to validate these associations in independent populations and to elucidate the biological mechanisms underlying the observed increased mortality associated with KSHV infection.

Association between human herpesvirus 8 and lipid profile in northwest China: A cross-sectional study.

Human herpesvirus 8 (HHV-8) infection shows obvious regional and ethnic differences. Although studies have shown that these differences may be associated with lipid metabolism, to date, no large-scale studies have explored this. This study explored the seropositivity rate of HHV-8 among 2516 residents from 10 regions of northwest China and then the correlates of HHV-8 infection with lipid profile. The HHV-8 serological positivity rate was 15.6% among all residents. The HHV-8 seroprevalence ranged 11.2-27.6% among different ethnicities. Across different BMI levels, the positive rates of HHV-8 were 27.6%, 16.9%, and 13.6% for a BMI < 18.5, 18.5-24.9, and ≥25, respectively. HHV-8 seropositivity rate was lower for hypertensive people (12.6%) than for non-hypertensive people (16.7%). Univariate logistic regression analyses revealed that age, hypertension, systolic blood pressure, BMI, total cholesterol, and high-density lipoprotein cholesterol (HDL-C) significantly correlated with HHV-8 seropositivity (p < 0.05). Multivariate logistic regression analysis after adjusting for confounding factors showed that HDL-C (odds ratio [OR]: 0.132, 95% confidence interval [CI], 0.082-0.212; p < 0.001) and BMI (OR: 0.959, 95% CI 0.933-0.986; p = 0.003) were associated with HHV-8 seropositivity. Subgroup analyses concerning ethnicity, sex, or age demonstrated a consistent relationship with HDL-C. The results of HHV-8 seropositivity and BMI were inconsistent in the subgroups. However, Spearman's correlation analysis between HHV-8 serum antibody titer and HDL-C levels showed no linear relationship among HHV-8 seropositive individuals (ρ = -0.080, p = 0.058). HHV-8 serum antibody titers were also not significantly correlated with BMI (ρ = -0.015, p = 0.381). Low HDL-C levels may be an independent risk factor for HHV-8 infection, but there is no significant correlation between HDL-C levels and HHV-8 antibody titers.

Outcomes in Kaposi's sarcoma-associated herpesvirus -associated primary effusion lymphoma and multicentric Castleman's disease in patients with human immunodeficiency virus (HIV) in a safety-net hospital system.

OBJECTIVE: To describe cases of Kaposi's sarcoma-associated herpesvirus (KSHV)-associated multicentric Castleman's disease (MCD) and primary effusion lymphoma (PEL) in patients with HIV from a large, safety-net hospital system in Dallas, Texas, USA. METHODS: We conducted a retrospective review of patients with HIV-associated PEL and/or MCD. RESULTS: Twelve patients with PEL and 10 patients with MCD were identified. All patients were male and 17 of 20 were men who have sex with men; 66.7% of PEL patients and 50% of MCD patients had concurrent KS at the time of diagnosis; 42% of patients with PEL and 20% of patients with MCD died during the follow-up period. We noted improved survival in our cohort compared to previous studies, particularly in our PEL patients with a median survival of 11.4 months compared to 3-6-month median survival historically. Median follow-up time for MCD patients was 17.5 months. This improved survival is despite suboptimal antiretroviral therapy (ART) adherence at diagnosis, with only 50% of patients on ART at the time of MCD/PEL diagnosis. CONCLUSION: These data highlight the importance of early recognition of PEL and MCD, and the larger-scale efforts needed to better understand the pathogenetic drivers of clinical outcomes in patients affected by KSHV-related diseases.

A variant of KSHV-associated inflammatory cytokine syndrome in elderly men of Mediterranean descent.

The spectrum of HHV-8-associated disorders includes Kaposi's sarcoma, primary effusion lymphoma, multicentric Castleman's disease, and the recently described KSHV inflammatory cytokine syndrome (KICS), a life-threatening disorder complicating HIV infection. There have been no reports in the literature concerning non-immunosuppressed individuals affected with KICS. We report here a KICS-like illness occurring in two elderly Greek men without HIV infection or other recognizable cause of immunosuppression.

Is human herpesvirus 8 infection more common in men than in women? an updated meta-analysis.

BACKGROUND: Clinically, most patients with Kaposi's sarcoma (KS) are male, and several direct and indirect mechanisms may underlie this increased susceptibility in men, Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), is considered to be the primary etiological agent responsible for KS. Thus, we propose the hypothesis that men are more susceptible to HHV-8 infection, leading to a higher incidence of Kaposi's sarcoma among males. A meta-analysis was conducted to evaluate the association between gender and HHV-8 seropositivity in the general population. METHODS: A comprehensive literature search was performed using 6 online databases: PubMed, EMBASE, Cochrane library, Web of Science, CNKI, and Wanfang. Studies published before March 15, 2023, were included. RESULTS: In all, 33 articles including 41 studies were included in the meta-analysis. In the included adult population. men had a higher risk of HHV-8 infection than did women in adult populations from all over the world (odds ratio [OR]: 1.08, 95% confidence interval [CI]: 1.01-1.15), but no differences were found in child population from all over the world (OR: 0.90, 95% CI: 0.79-1.01). There was a significant difference in HHV-8 seroprevalence between men and women in sub-Saharan Africa (SSA) adult population (OR: 1.15, 95% CI: 1.05-1.26). However, no significant differences were observed in sub-Saharan Africa (SSA) child population (OR: 0.90, 95%CI 0.78-1.03). As for other continents, the results showed no significant difference, such as the Asian population (OR: 1.03, 95%CI: 0.92-1.16). or the European and American populations (OR 1.01, 95%CI 0.87-1.17). CONCLUSION: There was a slight gender disparity for HHV-8 infection in the adult population. Among the adult populations from SSA and globally, men were more likely to be infected with HHV-8 than were women. However, no statistical significance was observed in the child populations from SSA and globally. In the future, the inclusion of more standardized studies may strengthen the results of this study.

HHV-8-associated diseases in transplantation: A case report and narrative review focused on diagnosis and prevention.

BACKGROUND: Human herpes virus 8 (HHV-8) or Kaposi sarcoma herpesvirus (KSHV) is an opportunistic oncovirus that causes multiple pathologic entities. METHODS: We present a case of fatal HHV-8-associated multisystem illness with disseminated Kaposi sarcoma and HHV8-associated lymphoproliferative disorder with systemic inflammation. We conducted a narrative review of the literature on HHV-8 in transplantation with a goal of illuminating the spectrum of HHV-8-associated diseases in this vulnerable population, modes of disease transmission, and the potential role for donor and recipient screening. RESULTS: HHV-8-associated KS, primary effusion lymphoma (PEL), multicentric Castleman disease (MCD), and KSHV inflammatory cytokine disorder (KICS) may affect transplant recipients; with the exception of KS, these conditions are rare but carry high morbidity and mortality. CONCLUSION: HHV-8-associated diseases have diverse and protean manifestations in transplant recipients, with potentially fatal outcomes. HHV-8 seroprevalence among organ donors and the magnitude of risk for donor-derived HHV-8 infection or clinically significant disease remain unknown and require further study.

Immune Deficiency/Dysregulation Associated Lymphoid Proliferations, EBV+ In Persons Living With HIV.

Background: The 5th edition of the World Health Organization Classification of Hematolymphoid Tumors recently defined immune deficiency/dysregulation (IDD)-associated-lymphoid-proliferations in HIV settings, where information is scarce, often gone under or misdiagnosed. Objectives: To describe the clinical picture, histopathology, and outcomes of IDD-associated-lymphoidproliferations Epstein-Barr virus+ (EBV) in people living with HIV without organ transplantation, antiretroviral therapy (ART) treated. Materials and Methods: HIV+ patients diagnosed with IDD-associated-lymphoid-proliferations seen at an academic medical center in Mexico from 2016 to 2019 were included. Immunohistochemical studies, in situ hybridization, and polymerase chain reaction analysis for EBV and LMP1 gene deletions were performed and correlated with clinical data. Results: We included 27 patients, all men who have sex with men, median age 36 years (interquartile range [IQR] 22-54). The median baseline CD4+ T cells were 113/mL (IQR 89-243), the CD4+/CD8+ ratio was 0.15 (IQR: 0.09-0.22), and the HIV viral load was 184,280 copies/mL (IQR: 76,000-515,707). Twenty patients (74.07%) had IDD-associated-lymphoid-proliferations hyperplasia plasma cell type EBV+, 3 (11.1%) had hyperplasia mononucleosis-like type (IM-type), 1 patient (3.70%) had florid follicular hyperplasia, 3 (11.1%) IDD-associated-lymphoid-proliferations polymorphic type, and there were 22 cases (81.4%) of synchronic Kaposi Sarcoma. Two patients were diagnosed with Hodgkin lymphoma following a second positron emission tomography-computed tomography scan-guided biopsy. The median follow-up was 228 weeks (IQR 50-269); 6 patients died (22.2%) of causes unrelated to IDD-associated-lymphoid-proliferations related. Conclusion: IDD-associated-lymphoid-proliferations EBV+ occured in severely immunosuppressed HIV+ patients, a high percentage of whom had concomitant Kaposi sarcoma. The prognosis was good in patients treated only with ART.

[Diffuse large B-cell lymphoma concurrent with Kaposi's sarcoma in the same lymph node in a human immunodeficiency virus-negative patient].

An 80-year-old Japanese man presented with systemic lymphadenopathy, including the para-aortic area and left inguinal nodes, which was diagnosed as diffuse large B-cell lymphoma (DLBCL) and human herpesvirus (HHV) 8-positive/HIV-negative Kaposi's sarcoma (KS). Immunohistochemical examination revealed that the lymphoma cells were negative for HHV-8. The patient received combined chemotherapy with rituximab, pirarubicin, cyclophosphamide, vincristine, and prednisolone for six cycles and achieved complete remission. In the literature, five cases of simultaneous appearance of malignant lymphoma and KS in the same lymph node have been reported, but DLBCL as a histological subtype has not yet been reported.

Prevalence, Incidence, and Predictors of Kaposi Sarcoma-associated Herpesvirus Infection Among Young Men Who Have Sex with Men in the Southern United States.

Kaposi Sarcoma (KS) continues to cause substantial morbidity and mortality in populations at risk in the southern US. Utilizing biospecimens from the Houston site of the Young Men's Affiliate Project, 351 men who have sex with men had blood tested for Kaposi Sarcoma-associated herpesvirus (KSHV) IgG. Measuring seroprevalence, seroconversion between timepoints, and demographic and clinical correlates, KSHV prevalence was 36.7% and incidence was 8.9 per 100 person-years, prevalence and incidence were higher among Black individuals, people living with HIV, and those with a history of syphilis. Further research on KSHV risk may improve health disparities in KS diagnosis and outcomes.

Deconstructing the liquid architecture of human herpesvirus 8 diseases.

Human herpesvirus 8 (HHV-8), also called Kaposi sarcoma herspesvirus (KSHV), causes several human tumours, which may be associated with systemic inflammation and body cavity effusions, including a form of multicentric Castleman disease (MCD) and a novel inflammatory syndrome, KSHV inflammatory cytokine syndrome (KICS). In this issue, Zhou et al. demonstrate that HHV-8-infected lambda-restricted plasmablasts can be detected in these effusions and can be used to distinguish MCD from other HHV-8 tumours as well as to categorise KICS into distinct clinicopathological groups. These findings open a path to an integrated clinicopathological approach to HHV-8-associated inflammatory diseases and may have clinical implications. Commentary on: Zhou et al. A novel approach for characterisation of KSHV-associated multicentric Castleman disease from effusions. Br J Haematol 2023;200:462-475.

A basic charge cluster near the C-terminus of the cytoplasmic tail contributes to the molecular stability of human herpesvirus 8 E3 ubiquitin ligases.

Human herpesvirus 8 (HHV8; also known as Kaposi's sarcoma-associated herpesvirus [KSHV]) utilizes the viral E3 ubiquitin ligase family members K3 and K5 for immune evasion. Both K3 and K5 mediate the ubiquitination of host MHC class I (MHC-I) molecules, which play a key role in antigen presentation to cytotoxic T lymphocytes (CTLs). Because ubiquitinated MHC-I is immediately down-regulated from the cell surface, HHV8-infected cells can escape surveillance by CTLs. K3 and K5 have similar domain structures and topologies. They contain an N-terminal RINGv ubiquitin ligase domain, two transmembrane helices, and an intrinsically disordered cytoplasmic tail at the C-terminus. The cytoplasmic tail contains a membrane-proximal "conserved region" involved in ligase activity. On the other hand, the role of the membrane-distal region of the cytoplasmic tail, termed the "C-tail" in this study, remains unclear. Here, we demonstrate that the C-tail contributes to the protein expression of both K3 and K5. The C-tail-truncated K3 and K5 mutants were rapidly reduced in cells. The recombinant C-tail proteins bind to acidic lipids via a basic charge cluster located near the C-terminus of the C-tails. Similar to the C-tail-truncated mutants, the basic charge cluster-substituting mutants showed decreased protein expression of K3 and K5. These findings suggest that the basic charge cluster near the C-terminus of the cytoplasmic tail contributes to the molecular stability of K3 and K5.

[Primary effusion lymphoma-like lymphoma transformed to diffuse large B-cell lymphoma].

A rare kind of malignant lymphoma, called primary effusion lymphoma (PEL) is associated with human herpesvirus 8 (HHV-8), and characterized by lymphomatous effusion in the bodily cavities. Although the initial clinical presentation of primary effusion lymphoma-like lymphoma (PEL-LL) is similar to that of PEL, PEL-LL is HHV-8 negative and has a favorable prognosis. A PEL-LL diagnosis was made after an 88-year-old man was admitted to our hospital with a pleural effusion. His disease regressed after effusion drainage. He demonstrated disease progression to diffuse large B-cell lymphoma after two years and ten months. Our example demonstrates that aggressive B-cell lymphoma can develop from PEL-LL.

Systematic analysis of Kaposi's sarcoma (KS)-associated herpesvirus genomes from a KS case-control study in Cameroon: Evidence of dual infections but no association between viral sequence variation and KS risk.

In sub-Saharan Africa, Kaposi's sarcoma-associated herpesvirus (KSHV) is endemic, and Kaposi's sarcoma (KS) is a significant public health problem. Until recently, KSHV genotype analysis was performed using variable gene regions, representing a small fraction of the genome, and thus the contribution of sequence variation to viral transmission or pathogenesis are understudied. We performed near full-length KSHV genome sequence analysis on samples from 43 individuals selected from a large Cameroonian KS case-control study. KSHV genomes were obtained from 21 KS patients and 22 control participants. Phylogenetic analysis of the K1 region indicated the majority of sequences were A5 or B1 subtypes and all three K15 alleles were represented. Unique polymorphisms in the KSHV genome were observed including large gene deletions. We found evidence of multiple distinct KSHV genotypes in three individuals. Additionally, our analyses indicate that recombination is prevalent suggesting that multiple KSHV infections may not be uncommon overall. Most importantly, a detailed analysis of KSHV genomes from KS patients and control participants did not find a correlation between viral sequence variations and disease. Our study is the first to systematically compare near full-length KSHV genome sequences between KS cases and controls in the same endemic region to identify possible sequence variations associated with disease risk.

HOPE in action: A prospective multicenter pilot study of liver transplantation from donors with HIV to recipients with HIV.

Liver transplantation (LT) from donors-with-HIV to recipients-with-HIV (HIV D+/R+) is permitted under the HOPE Act. There are only three international single-case reports of HIV D+/R+ LT, each with limited follow-up. We performed a prospective multicenter pilot study comparing HIV D+/R+ to donors-without-HIV to recipients-with-HIV (HIV D-/R+) LT. We quantified patient survival, graft survival, rejection, serious adverse events (SAEs), human immunodeficiency virus (HIV) breakthrough, infections, and malignancies, using Cox and negative binomial regression with inverse probability of treatment weighting. Between March 2016-July 2019, there were 45 LTs (8 simultaneous liver-kidney) at 9 centers: 24 HIV D+/R+, 21 HIV D-/R+ (10 D- were false-positive). The median follow-up time was 23 months. Median recipient CD4 was 287 cells/µL with 100% on antiretroviral therapy; 56% were hepatitis C virus (HCV)-seropositive, 13% HCV-viremic. Weighted 1-year survival was 83.3% versus 100.0% in D+ versus D- groups (p = .04). There were no differences in one-year graft survival (96.0% vs. 100.0%), rejection (10.8% vs. 18.2%), HIV breakthrough (8% vs. 10%), or SAEs (all p > .05). HIV D+/R+ had more opportunistic infections, infectious hospitalizations, and cancer. In this multicenter pilot study of HIV D+/R+ LT, patient and graft survival were better than historical cohorts, however, a potential increase in infections and cancer merits further investigation.

Phase II single-arm study of nivolumab and ipilimumab (Nivo/Ipi) in previously treated classical Kaposi sarcoma (cKS).

BACKGROUND: Classical Kaposi sarcoma (cKS) is a rare human herpesvirus 8-associated sarcoma with limited treatment options. We evaluated the efficacy and safety of nivolumab in combination with ipilimumab in patients with previously treated progressive cKS. PATIENTS AND METHODS: cKS patients with progressive disease after one or more lines of systemic therapy and measurable disease by positron emission tomography/computed tomography and/or physical examination received nivolumab 240 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks until progression or toxicity for a maximum of 24 months. The primary endpoint was overall response rate; secondary endpoints included 6-month progression-free survival (PFS) rate and safety. Immune correlates were explored using immunohistochemistry, DNA sequencing (596/648 genes) and RNA sequencing (whole transcriptome hybrid capture) of tumor specimens and matched blood. RESULTS: Eighteen male patients (median age 76.5 years) were enrolled between April 2018 and December 2020. At a median follow up of 24.4 months, overall response rate by RECIST v1.1 was 87%. Metabolic complete response as assessed by positron emission tomography/computed tomography was observed in 8 of 13 (62%) assessable patients. Some 6/13 achieved pathological complete response after treatment. In two patients, palliative limb amputation was prevented. Median PFS was not reached. The 6- month and 12-month PFS rate was 76.5% and 58.8%, respectively. Only four patients (22%) experienced grade 3-4 adverse events. The most frequent genomic alteration was biallelic copy number loss of the FOX1A gene. The majority of tumors carried a low tumor mutational burden, were microsatellite stable, mismatch repair proficient, did not express programmed death-ligand 1, and displayed only low lymphocytic infiltrates, rendering them immunologically 'cold'. CONCLUSIONS: This prospectively designed phase II study of nivolumab and ipilimumab demonstrates promising activity of this combination in progressive cKS representing a new treatment option in this population.

Long-term outcomes for children and adolescents with Kaposi sarcoma.

OBJECTIVES: Kaposi sarcoma (KS) is one of the most common childhood cancers in eastern and central Africa. It has become a treatable disease with increasing availability of antiretroviral therapy (ART) and chemotherapy. We aimed to fill the data gap in establishing whether long-term survival is achievable for children in low-income countries. METHODS: We retrospectively analysed data for children and adolescents aged ≤ 18.9 years diagnosed with HIV-related or endemic KS from 2006 to 2015 who received standardized institutional treatment regimens utilizing chemotherapy plus ART (if HIV-positive) at a tertiary care public hospital in Lilongwe, Malawi. Long-term survival was analysed and mortality was associated with KS for those with refractory/progressive disease at the time of death. RESULTS: There were 207 children/adolescents with KS (90.8% HIV-related); 36.7% were alive, 54.6% had died, and 8.7% had been lost to follow-up. The median follow-up time for survivors was 6.9 years (range 4.2-13.9 years). Death occurred at a median of 5.3 months after KS diagnosis (range 0.1-123 months). KS progression was associated with mortality for most (61%) early deaths (survival time of < 6 months); conversely, KS was associated with a minority (31%) of late-onset deaths (after 24 months). The 7-year overall survival was 37% [95% confidence interval (CI) 30-44%] and was higher for those diagnosed between 2011 and 2015 compared to 2006-2010: 42% (95% CI 33-51%) versus 29% (95% CI 20-39%), respectively (P = 0.01). Among the 66 HIV-positive survivors, 58% were still on first-line ART. CONCLUSIONS: Long-term survival is possible for pediatric KS in low-resource settings. Despite better survival in more recent years, there remains room for improvement.

Seroprevalence of Kaposi's sarcoma-associated herpesvirus and risk factors in Jiuquan area, China.

The seroprevalence of Kaposi's sarcoma-associated herpesvirus (KSHV) is high in Xinjiang, China. But the seroprevalence of KSHV and risk factors are still unknown in Gansu which is adjacent to Xinjiang. Six hundred and seventy-eight serum samples of the general population and 87 serum samples of syphilis patients from Jiuquan, Gansu were tested for antibodies against KSHV, including one latent protein (ORF73) and two lytic proteins (ORF65 and K8.1) using the ELISA. The total KSHV-seropositive rate was 15.9% in 678 serum samples in the Jiuquan area, and the KSHV-seropositive rate of males was higher than females (18.0% vs. 14.6%, p > 0.05). The Uygur, Kazakh, Hui, Manchu, and Mongolian populations had a higher seroprevalence of KSHV than the Han population (43.8%, 40.0%, 34.5%, 30.3%, 35.0% vs. 11.0%, respectively) among the ethnic groups in Jiuquan. Compared to the Han, Uygur, Kazak, Hui, Manchu, and Mongolian people had an increase in the risk of KSHV of 528.9%, 439.1%, 325.6%, 251.6%, and 335.4% (p < 0.001, p < 0.001, p < 0.001, p = 0.002, p = 0.003, respectively). The serum prevalence of KSHV in subjects aged < 20 years, 20-50 years, and >50 years was 13.8%, 14.7%, and 20.1%, respectively. Compared to the subjects aged < 20 years, 20-50 years and >50 years had an increase in the risk of KSHV of 7.4% and 56.9% (p = 0.829 and p = 0.204, respectively). Compared to the positive rate of KSHV in the general population of Anhui, the positive rate of KSHV was significantly higher in the general population of the Jiuquan area (15.9% vs. 9%, p < 0.01). There was no significant difference in the positive rate of KSHV between the Han population of Jiuquan and the Han population of Anhui (p > 0.05). In the population of syphilis patients in the Jiuquan area, the positive rate of KSHV was 30.7%, which was higher than that of the general population in the Gansu area (p < 0.05). This study indicates that Gansu has a high seroprevalence of KSHV. Ethnicity and syphilis are risk factors for KSHV infection.