Clinical Features and Outcomes of Patients With Symptomatic Kaposi Sarcoma Herpesvirus (KSHV)-associated Inflammation: Prospective Characterization of KSHV Inflammatory Cytokine Syndrome (KICS)

Polizzotto, Mark N.; Uldrick, Thomas S.; Wyvill, Kathleen M.; Aleman, Karen; Marshall, Vickie; Wang, Victoria; Whitby, Denise; Pittaluga, Stefania; Jaffe, Elaine S.; Millo, Corina; Tosato, Giovanna; Little, Richard F.; Steinberg, Seth M.; Sereti, Irini; Yarchoan, Robert

doi:10.1093/cid/civ996

Cited by 164 publications

(199 citation statements)

References 29 publications

Supporting

Mentioning

185

Contrasting

Unclassified

Order By: Relevance

“…Elevations in KSHV VL and circulating levels of human and viral IL-6 have an established role in the biology of KSHV, particularly in MCD, KICS, and primary effusion lymphoma. [9][10][11][12][13]16,17 We hypothesized that KSHV viremia and Median IL-6 Level, pg/mL 1 10.81 7.70 0.62 n/a n/a n/a IL-6 Level > 8.5 pg/mL, n (%) 2 7 (58%) 2 (33%) 0.62 n/a n/a n/a KSHV Viral Load Detectable, n 2 n/a n/a n/a 7 (78%) 5 (56%) 0.62…”

Section: Discussionmentioning

confidence: 99%

“…14 Features of KSHV lytic activation-including elevated KSHV viral load (VL) and IL-6 levels-are characteristic of KSHV-associated lymphoproliferative disorders such as MCD, KICS, and primary effusion lymphoma. [9][10][11][12][15][16][17] Molecular profiling studies of KSHV transcription in adult KS patients in Malawi as well as the United States uncovered substantial heterogeneity. 14 20 Acknowledging the prominence of lymphadenopathic KS in children living in KSHV-endemic regions of Africa, and the potentially distinct biological mechanisms of disease in this region, we sought to explore virologic characteristics of pediatric KS and potential clinical associations.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

KSHV viral load and Interleukin‐6 in HIV‐associated pediatric Kaposi sarcoma—Exploring the role of lytic activation in driving the unique clinical features seen in endemic regions

El‐Mallawany

Mehta

Kamiyango³

et al. 2018

Intl Journal of Cancer

View full text Add to dashboard Cite

Kaposi sarcoma (KS) is among the most common childhood malignancies in central, eastern, and southern Africa. Although its unique clinical features have been established, biological mechanisms related to the causative agent, KS-associated herpes-virus (KSHV), have yet to be explored in children. We performed a prospective observational pilot study to explore associations between KSHV viral load (VL), human interleukin-6 (IL-6) and IL-10 levels, and clinical characteristics of 25 children with KS in Lilongwe, Malawi from June 2013-August 2015. The median age was 6.4 years. Lymphadenopathy was the most common site of KS involvement (64%), followed by skin and oral mucosa (44% each), woody edema (12%), and pulmonary (8%). Baseline samples for plasma KSHV VL, IL-6 and IL-10 analyses were available for 18/25 patients (72%) at time of KS diagnosis. KSHV VL was detectable at baseline in 12/18 (67%) patients, the median baseline IL-6 level was 8.53 pg/mL (range 4.31-28.33), and the median baseline IL-10 level was 19.53 pg/mL (range 6.91-419.69). Seven (39%) patients presented with an IL-6 level > 10 pg/mL (exceeding twice the upper limit of normal). Detectable KSHV VL was significantly associated with lymphadenopathic KS (p = 0.004), while having undetectable KSHV VL was associated with a higher likelihood of presenting with hyperpigmented skin lesions (p = 0.01). Detectable KSHV VL and elevated IL-6 levels are present in a subset of children with KS. Lytic activation of KSHV and associated elevation in KSHV VL may contribute to the unique clinical manifestations of pediatric KS in KSHV-endemic regions of Africa.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

KSHV viral load and Interleukin‐6 in HIV‐associated pediatric Kaposi sarcoma—Exploring the role of lytic activation in driving the unique clinical features seen in endemic regions

El‐Mallawany

Mehta

Kamiyango³

et al. 2018

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…In addition to KS, KSHV is also the etiologic agent of the plasmablastic variant of multicentric Castleman's disease (MCD) (6) and primary effusion lymphoma (PEL) (7,8). Moreover, KSHV is the causative agent of KS-immune reconstitution syndrome (KS-IRIS) (9,10) and KSHV-inflammatory cytokine syndrome (KICS) (11). However, not all KSHV infections lead to KSHV-associated conditions.…”

Section: Introductionmentioning

confidence: 99%

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

Dittmer

Damania

2016

Journal of Clinical Investigation

181

152

View full text Add to dashboard Cite

“…KSHV has also been shown to be the cause of KSHV inflammatory cytokine syndrome (KICS) [11,12]. KSHV’s ~160 Kbp DNA genome [13,14] is closely related to γ-1 EBV, and the γ-2 herpesvirus saimiri (HVS) and Rhesus monkey rhadinovirus (RRV) [15].…”

Section: Introductionmentioning

confidence: 99%

KSHV Entry and Trafficking in Target Cells—Hijacking of Cell Signal Pathways, Actin and Membrane Dynamics

Kumar

Chandran

2016

Viruses

View full text Add to dashboard Cite

Kaposi’s sarcoma associated herpesvirus (KSHV) is etiologically associated with human endothelial cell hyperplastic Kaposi’s sarcoma and B-cell primary effusion lymphoma. KSHV infection of adherent endothelial and fibroblast cells are used as in vitro models for infection and KSHV enters these cells by host membrane bleb and actin mediated macropinocytosis or clathrin endocytosis pathways, respectively. Infection in endothelial and fibroblast cells is initiated by the interactions between multiple viral envelope glycoproteins and cell surface associated heparan sulfate (HS), integrins (α3β1, αVβ3 and αVβ5), and EphA2 receptor tyrosine kinase (EphA2R). This review summarizes the accumulated studies demonstrating that KSHV manipulates the host signal pathways to enter and traffic in the cytoplasm of the target cells, to deliver the viral genome into the nucleus, and initiate viral gene expression. KSHV interactions with the cell surface receptors is the key platform for the manipulations of host signal pathways which results in the simultaneous induction of FAK, Src, PI3-K, Rho-GTPase, ROS, Dia-2, PKC ζ, c-Cbl, CIB1, Crk, p130Cas and GEF-C3G signal and adaptor molecules that play critical roles in the modulation of membrane and actin dynamics, and in the various steps of the early stages of infection such as entry and trafficking towards the nucleus. The Endosomal Sorting Complexes Required for Transport (ESCRT) proteins are also recruited to assist in viral entry and trafficking. In addition, KSHV interactions with the cell surface receptors also induces the host transcription factors NF-κB, ERK1/2, and Nrf2 early during infection to initiate and modulate viral and host gene expression. Nuclear delivery of the viral dsDNA genome is immediately followed by the host innate responses such as the DNA damage response (DDR), inflammasome and interferon responses. Overall, these studies form the initial framework for further studies of simultaneous targeting of KSHV glycoproteins, host receptor, signal molecules and trafficking machinery that would lead into novel therapeutic methods to prevent KSHV infection of target cells and consequently the associated malignancies.

show abstract

Clinical Features and Outcomes of Patients With Symptomatic Kaposi Sarcoma Herpesvirus (KSHV)-associated Inflammation: Prospective Characterization of KSHV Inflammatory Cytokine Syndrome (KICS)

Cited by 164 publications

References 29 publications

KSHV viral load and Interleukin‐6 in HIV‐associated pediatric Kaposi sarcoma—Exploring the role of lytic activation in driving the unique clinical features seen in endemic regions

KSHV viral load and Interleukin‐6 in HIV‐associated pediatric Kaposi sarcoma—Exploring the role of lytic activation in driving the unique clinical features seen in endemic regions

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

KSHV Entry and Trafficking in Target Cells—Hijacking of Cell Signal Pathways, Actin and Membrane Dynamics

Contact Info

Product

Resources

About