Human Herpesvirus 8 (HHV8) Sequentially Shapes the NK Cell Repertoire during the Course of Asymptomatic Infection and Kaposi Sarcoma

Jan 2012

Stéphanie Dupuy, Marion Lambert, David Zucman, Siméon-Pierre Choukem,^3,¤ Sara Tognarelli,¹ Cécile Pages, Céleste Lebbé, and Sophie Caillat-Zucma

Abstract

The contribution of innate immunity to immunosurveillance of the oncogenic Human Herpes Virus 8 (HHV8) has not been studied in depth. We investigated NK cell phenotype and function in 70 HHV8-infected subjects, either asymptomatic carriers or having developed Kaposi's sarcoma (KS). Our results revealed substantial alterations of the NK cell receptor repertoire in healthy HHV8 carriers, with reduced expression of NKp30, NKp46 and CD161 receptors. In addition, down-modulation of the activating NKG2D receptor, associated with impaired NK-cell lytic capacity, was observed in patients with active KS. Resolution of KS after treatment was accompanied with restoration of NKG2D levels and NK cell activity. HHV8-latently infected endothelial cells overexpressed ligands of several NK cell receptors, including NKG2D ligands. The strong expression of NKG2D ligands by tumor cells was confirmed in situ by immunohistochemical staining of KS biopsies. However, no tumor-infiltrating NK cells were detected, suggesting a defect in NK cell homing or survival in the KS microenvironment. Among the known KS-derived immunoregulatory factors, we identified prostaglandin E2 (PGE2) as a critical element responsible for the down-modulation of NKG2D expression on resting NK cells. Moreover, PGE2 prevented up-regulation of the NKG2D and NKp30 receptors on IL-15-activated NK cells, and inhibited the IL-15-induced proliferation and survival of NK cells. Altogether, our observations are consistent with distinct immunoevasion mechanisms that allow HHV8 to escape NK cell responses stepwise, first at early stages of infection to facilitate the maintenance of viral latency, and later to promote tumor cell growth through suppression of NKG2D-mediated functions. Importantly, our results provide additional support to the use of PGE2 inhibitors as an attractive approach to treat aggressive KS, as they could restore activation and survival of tumoricidal NK cells.

Complete Text:

NIH/PLOS

Opposing Regulation of PROX1 by Interleukin-3 Receptor and NOTCH Directs Differential Host Cell Fate Reprogramming by Kaposi Sarcoma Herpes Virus

June 2012

Jaehyuk Yoo,^#1 Ha Neul Lee,^#1 Inho Choi,¹ Dongwon Choi,¹ Hee Kyoung Chung,¹ Kyu Eui Kim,¹Sunju Lee,¹ Berenice Aguilar,¹ Jinjoo Kang,¹ Eunkyung Park,¹ Yong Suk Lee,¹ Yong-Sun Maeng,¹Nam Yoon Kim,¹ Chester J. Koh,² and Young-Kwon Hong^1,*

^Abstract

^{Lymphatic endothelial cells (LECs) are differentiated from blood vascular endothelial cells (BECs) during embryogenesis and this physiological cell fate specification is controlled by PROX1, the master regulator for lymphatic development. When Kaposi sarcoma herpes virus (KSHV) infects host cells, it activates the otherwise silenced embryonic endothelial differentiation program and reprograms their cell fates. Interestingly, previous studies demonstrated that KSHV drives BECs to acquire a partial lymphatic phenotype by upregulating PROX1 (forward reprogramming), but stimulates LECs to regain some BEC-signature genes by downregulating PROX1 (reverse reprogramming). Despite the significance of this KSHV-induced bidirectional cell fate reprogramming in KS pathogenesis, its underlying molecular mechanism remains undefined. Here, we report that IL3 receptor alpha (IL3Rα) and NOTCH play integral roles in the host cell type-specific regulation of PROX1 by KSHV. In BECs, KSHV upregulates IL3Rα and phosphorylates STAT5, which binds and activates the PROX1 promoter. In LECs, however, PROX1 was rather downregulated by KSHV-induced NOTCH signal via HEY1, which binds and represses the PROX1 promoter. Moreover, PROX1 was found to be required to maintain HEY1 expression in LECs, establishing a reciprocal regulation between PROX1 and HEY1. Upon co-activation of IL3Rα and NOTCH, PROX1 was upregulated in BECs, but downregulated in LECs. Together, our study provides the molecular mechanism underlying the cell type-specific endothelial fate reprogramming by KSHV.}

^{Author Summary}

^{Kaposi's sarcoma (KS) is one of the most common neoplasms in HIV-positive individuals and organ transplant recipients. KS-associated herpes virus (KSHV), also known as human herpes virus (HHV)-8, has been identified as the causative agent and infects endothelial cells to form KS. Importantly, we and others have discovered that when KSHV infects endothelial cells of blood vessels, it reprograms host cells to resemble endothelial cells in lymphatic vessels. On the other hand, when KSHV infects endothelial cells in lymphatic vessels, the virus directs the host cells to partially obtain the phenotypes of blood vessel endothelial cells. These host cell reprogramming represent abnormal pathological processes, which are not as complete as the physiological process occurring during embryonic development. Currently, it is not clear how and why this cancer causing virus modifies the fate of its host cells. In this study, we aimed to dissect the molecular mechanism underlying the virus-induced host cell fate reprogramming and found two important cellular signaling pathways, interleukin-3 and Notch, playing key roles in the pathological events. Our current study provides a better understanding of KS tumorigenesis with a potential implication in a new KS therapy.}

Full Text Article

NIH-PLOS One

Variable clinical presentations of Classic Kaposi Sarcoma in Turkish patients

March 2012

Ilknur Altunay, Asli Kucukunal,^* Gulsen Tukenmez Demirci, and Bilge Ates

Abstract

Key Words: HHV-8, HIV, Kaposi sarcoma, skin cancer

Background

Kaposi sarcoma (KS) is a vascular neoplasm with multicentric cutanenous and extracutaneous involvements, which was first described by Moriz Kaposi in 1872. Since then, different epidemiological clinical and histopathological variants of this neoplasm have been identified. Classic Kaposi sarcoma (CKS) is one of four main clinico-epidemiologiologic variants. characteristics of the disease.

Materials and Methods

Four Turkish inpatients with CKS were evaluated in the study. All medical history and clinical data were noted. A screening immunodeficiency workup were performed for all patients. HHV-8 immunofluorescence testing on the specimens and ELISA test for human immunodeficiency virus (HIV 1 and 2) were performed. Pulmonary X ray graphies and computurized tomography (CT) scan were applied. Stage of the tumor was determined, in each case, according to the classification system proposed by Brambilla et al in 2003.

Results

All patients are positive for HHV-8. They were all immunocompetent and negative for HIV1 and HIV2. The first patient was unusual for morphological presentation of several verrucoid lesions that was evaluated as verrucoid KS. He was considered stage IB CKS. The patient 2 was a young man and the course of KS seemed unexpectedly aggressive for CKS. His clinical appearence seemed us to be a patient with AIDSassociated KS. The patient was evaluated as stage IVB CKS. Our third patient had also prominent lymphedema associated with bluish discoloration on the toes and fingers, suggesting a diagnosis of peripheral vascular disorder. He was diagnosed as stage IIIB CKS. The fourth case was interesting for very extensive lesions involving big sized plaques and also the existence of mucosal lesion. The patient was diagnosed as stage IVB CKS.

Conclusions

It seems that the reports of exceptional cases of KS are accumulating. Data from various cases should be collected and perhaps, novel clinical classifications should be considered. 

Full Text Article

NIH - Journal of Dermatological Case Reports

Classic kaposi sarcoma with pulmonary involvement mimicking endobronchial tuberculosis in a child.

July 2012

Cakir FB, Cakir E, Tuzuner N, Kut A.

Source

Department of Pediatric Hematology-Oncology, Bezmialem Vakif University, Istanbul, Turkey.

Abstract

Key Words: Kaposi' sarcoma; child, endobronchial lesion, pulmonary

Kaposi' sarcoma (KS) is a low-grade vascular neoplasm and classic KS, a subtype of KS, is extremely rare in children. Childhood pulmonary involvement in classic KS has not been reported in the literature. We describe an HIV-seronegative pediatric case with a fulminant course of classic KS with pulmonary involvement mimicking endobronchial tuberculosis. 

Wiley OnLine

Many Common Cancers Are Sparked by Viruses

Researchers have found that a significant portion of cancers are triggered by viruses.

BY MAKINI BRICE | DEC 06, 2012 06:03 

Many people believe that cancers are caused by a person's diet, bad habits, or chemicals. However, researchers have found that a significant portion of cancers are triggered by viruses. The good news is that the viruses can be stopped if scientists get to them in time and break the link. The bad news is that we are not yet completely there.

Over 50 years ago, an Irish doctor named Denis Burkitt opened up a clinic in Uganda. Nearly immediately, he realized that a large number of children who were visiting his facility had facial swellings that could become large enough to choke and kill. He later dubbed the cancer Burkitt's lymphoma.

Burkitt's lymphoma is the most common childhood cancer in Africa and it is thought to be triggered by an infection. The disease is associated with Epstein-Barr virus. 95 percent of adults in the United States have the virus, according to Centers for Disease Control and Prevention. Malaria is also considered to play a role.

This is not the only virus-cancer link. H. pylori is a strain of bacteria that causes ulcers and can sometimes cause stomach cancer. The parasite that causes schistosomiasis can also trigger stomach cancer. A virus that attacks people with weak immune systems has also been known to cause Kaposi's sarcoma, a cancerous tumor that targets the connective tissue.

In North America, only 1 in 25 cancers are caused by infections. In developing countries, that rate is up to 1 in 3, mostly because poor sanitation puts people at greater risk for contact with germs.

The infectious agents invade cells and disrupt their normal behavior. Epstein-Barr, for example, invades B cells and forces them to grow. The more they grow, the more likely it is that the cell makes a mistake.

Already, doctors are performing work to stop the link between viruses and cancer. Look at the human papilloma virus vaccine, for example. The controversial HPV vaccine has been known to target a virus linked with cervical cancer. The vaccine is an effort by public health advocates to lower the rates of cervical cancer infection.

Medical Daily

Predictive Clinical Factors in the Diagnosis of Gastrointestinal Kaposi's Sarcoma and Its Endoscopic Severity.

2012

Nagata N, Shimbo T, Yazaki H, Asayama N, Akiyama J, Teruya K, Igari T, Ohmagari N, Oka S, Uemura N.

Source

Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan.

Abstract

BACKGROUND:

The diagnosis of gastrointestinal (GI) involvement in Kaposi's sarcoma (KS) is important to make because the need for treatment depends on the extent of the disease. Moreover, severe GI lesions can cause serious complications. Endoscopy with biopsy is an extremely useful method to diagnose GI-KS. However, determining the indications for endoscopy is difficult because KS can occur without GI symptoms or cutaneous KS. This study sought to clarify predictive clinical factors for GI-KS and its severity on endoscopy.

METHODOLOGY/PRINCIPAL FINDINGS:

A total of 1,027 HIV-infected patients who underwent endoscopy were analyzed. Sexual behavior, CD4 count, HIV RNA, history of highly active antiretroviral therapy (HAART), GI symptoms, and cutaneous KS were assessed. Endoscopic severity including bulky tumor, ulceration, and number of lesions were evaluated. Thirty-three patients had GI-KS and 46 patients cutaneous KS. Among the GI-KS patients, 78.8% (26/33) had no GI symptoms and 24.2% (8/33) had no cutaneous KS. Univariate analysis identified men who have sex with men (MSM), CD4  copies/mL, no history of HAART, and cutaneous KS were significantly associated with GI-KS. 

Among the GI-KS patients, 78.8% - twentysix of thirty three - had no GI symptoms and 24.2%  had no cutaneous KS. Univariate analysis identified men who have sex with men (MSM), CD4  less then 100 cells/µL, HIV RNA  plus minus 10,000 copies/mL, no history of HAART, and cutaneous KS were significantly associated with GI-KS. Among these factors, cutaneous KS was closely related to GI-KS on multivariable analysis. Among patients without cutaneous KS, MSM and CD4 count less then 100 cells/µL were the only independent clinical factors related to GI-KS. Bulky tumor was significantly associated with CD4  100 cells/µL and large number of lesions was significantly associated with HIV-RNA.

CONCLUSIONS:

To diagnose GI-KS, clinical factors need to be considered before endoscopy. The presence of GI symptoms is not useful in predicting GI-KS. MSM and CD4 count  less then 100 cells/µL are predictive factors among patients without cutaneous KS. Caution should be exercised especially in patients with low CD4 counts or high HIV viral loads as they are more likely to develop severe GI-KS lesions.

PLOS|one

Disseminated bone lesions in AIDS-associated Kaposi sarcoma, a bad prognosis? About four cases.

Nov 2012

Wassilew N, Ciaffi L, Vu D, Calmy A, Toutous Trellu L.

Source

University Hospital Geneva, Infectious Diseases, Geneva, Switzerland.

Abstract

Kaposi sarcoma (KS) can present with a wide range of clinical features ranging from minimal cutaneous disease to a rapidly progressing neoplasm. Bone lesions are most often discovered accidently in the context of radiological investigations done for the screening of KS-visceral involvement [1]. Little is known on clinical outcome and response to antiretroviral therapy (ART) and/or chemotherapy of these lytic osseous lesions. We report four cases with bone involvement in the context of systemic KS and aim at describing the long-term clinical outcome in two of these patients. Cases of AIDS-associated KS with disseminated bone lesions were collected in the HIV Unit, University Hospital Geneva, Switzerland. 

Patients were compared on clinical, biological and radiological features and therapeutic responses. Between 2002 and 2012, four HIV1-infected patients with T1 stage of KS presented disseminated osseous lesions (Table 1). Mean age was 43 years (range 39 - 47 years), mean time of follow up until our analysis was 48.5 months (SD 53.8), and mean CD4 count at KS diagnosis was 190.5 c/mL (SD 202.8). All patients showed hypodense bone lesions predominating the axial skeleton (Figure 1), but no radiological imaging was performed to search for peripheral bone lesions.No patient reported pain or experienced pathological fractures. In one patient a dual-energy X-ray absorptiometry (DXA) showed a bone mineral density within normal range after 10 years of KS diagnosis with disseminated bone lesions. No radiological change was observed in that patient despite stable KS disease after 13 cycles of liposomal doxorubicin and ART (Figure 1). 

We describe a well-documented long-term follow up of disseminated osseous AIDS-associated KS disease. In our four cases, lytic bone lesions were asymptomatic and were not associated with bone fragility. We even could confirm the KS nature of the lesions by bone biopsy in patient B (3 months after KS diagnosis), as the differential diagnosis is wide, and include bacillary angiomatosis, cancers or metastasis. Chemotherapy and antiretroviral treatment did not affect bone lesions using CT scan despite a good response on other KS-affected sites. Prognostic factors are well established in AIDS-associated KS [2]; however disseminated bone disease does not seem to have an impact on disease evolution. A larger sample size is needed to confirm this hypothesis.

PubMed

Risk of Kaposi sarcoma during the first months on combination antiretroviral therapy.

Nov 2012

Lacombe JM, Boue F, Grabar S, Viget N, Gazaignes S, Lascaux-Cametz AS, Pacanowski J, Partisani M, Launay O,Matheron S, Rosenthal E, Rouveix E, Tattevin P, de Truchis P, Costagliola D, Goedert JJ.

Source

aInserm UMR-S 943; UPMC Univ Paris 06 UMR-S 943; INSERM-TRANSFERT; Paris, France bAP-HP, Hôpital Antoine Béclère, Service de médecine interne et d'immunologie clinique; Université Paris-Sud, Clamart, France cINSERM UMR-S 943; AP-HP, Groupe Hospitalier Cochin Hôtel-Dieu, Unité de biostatistique et épidémiologie; Université Paris Descartes, Paris, France dCentre Hospitalier de Tourcoing, Service universitaire des maladies infectieuses et du voyage, Tourcoing, France eAP-HP, Hôpital Saint Louis, Service des maladies infectieuses et tropicales, Paris, France fAP-HP, Hôpital Henri-Mondor, Service d'immunologie clinique, Créteil, France gAP-HP, Hôpital Saint Antoine, Service des maladies infectieuses et tropicales, Paris, France hHôpitaux Universitaires de Strasbourg, Le Trait d'Union - Centre de soins de l'infection par le VIH, Strasbourg, France iUniversité Paris Descartes; AP-HP, Hôpital Cochin, Paris, France jUniversité Denis Diderot Paris 7; AP-HP Hôpital Bichat-Claude Bernard, Service de Maladies infectieuses et Tropicales, Paris, France kHôpital l'Archet, Département de médecine interne; Université de Nice-Sophia Antipolis, Nice, France lHôpital Ambroise Paré, Service de médecine interne, Boulogne, France mCHU Pontchaillou, Service des Maladies Infectieuses et de Réanimation Médicale, Rennes, France nAP-HP, Hôpital Raymond Poincaré, Service de médecine aigue spécialisée, Garches, France oINSERM UMR-S 943; UPMC Univ Paris 06 UMR-S 943, Paris, France pDivision of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD USA.

Abstract

OBJECTIVE: Determine if incident AIDS-defining Kaposi sarcoma (KS) or Pneumocystis jiroveci pneumonia (PJP) is associated with combination antiretroviral therapy (cART) initiation. 

DESIGN: Compare risk for KS and PJP by time on cART and CD4 reconstitution. 

METHODS: In the FHDH-ANRS CO4 cohort (N = 66,369), KS (N = 1811) and PJP (N = 1718) incidence rates were computed by demographic and HIV strata. Crude and adjusted relative risk (RR) with 95% confidence intervals (CI) following cART initiation were calculated by Poisson regression with untreated patients during 1996-2009 as reference. CD4 counts were compared by Wilcoxon rank sum tests. 

RESULTS: KS risk was very high during months 1-3 on cART (N = 160, RRCrude 3.94, CI 3.26-4.76), which was incompletely attenuated by adjustment for demographics and contemporaneous CD4 count (RRAdj 1.25, CI 1.02-1.53). Corresponding PJP risk was minimally elevated (N = 84, RRCrude 1.80, CI 1.42-2.30) and markedly reduced with adjustment on the same variables and PJP prophylaxis (RRAdj 0.52, CI 0.41-0.67). HIV load had no added effect. Median CD4 cell count at cART initiation was much lower in patients with incident KS (82/mm) or PJP (61/mm) within 3 months compared with those without (>250/mm). Notably, median CD4 change was +44 cells/month with incident KS within 3 months of cART initiation versus 0 cells/month with incident PJP . 

CONCLUSIONS: Failure of CD4 reconstitution during months 1-3 on cART fully accounted for incident PJP. In contrast, there were 1.6 additional KS cases per 1000 person-years during months 1-3 on cART, suggesting that immune reconstitution may contribute to the risk for AIDS-defining KS.

Lippincott Williams Wilkins