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

Disseminated cutaneous Kaposi sarcoma in a patient receiving triptolide/tripdiolide for rheumatoid arthritis.

Aug  2012

Grzegorzewska AE, Frankiewicz D, Bręborowicz D, Matławska I, Bylka W.

Source

Chair and Department of Nephrology, Transplantology and Internal Diseases, Karol Marcinkowski University of Medical Sciences, Poznan, Poland. alicja_grzegorzewska@yahoo.com

Abstract

BACKGROUND:

To date, Kaposi sarcoma has not been mentioned among the adverse effects of triptolide/tripdiolide, ethyl acetate extracts or polyglycosides of the Chinese herbal remedy Tripterygium wilfordii Hook F.

CASE REPORT:

A patient was diagnosed with rheumatoid arthritis at the age of 29 years. She underwent treatment with corticosteroids, methotrexate and gold sodium thiosulfate, and was chronically taking ketoprofen. At the age of 59 years she started to take a powder (≈2 g/day) from a Chinese physician for treatment of rheumatoid arthritis. This powder was supplied to her regularly for 10 years. At the age of 69 years, multiple soft, violaceous to dark-red patches, plaques, nodules and blisters of varying sizes appeared on a background of severely edematous skin on her legs, and later on her arms. Biopsy specimens of the leg lesions were diagnostic for human herpesvirus 8-associated Kaposi sarcoma. Triptolide (235 µg/1 g) and tripdiolide were found in the Chinese powder by the use of Liquid Chromatography Electrospray Ionization Mass Spectrometry. Administration of the powder was stopped and medication with paclitaxel was introduced. General condition of the patient improved and skin lesions diminished significantly.

CONCLUSIONS:

This case indicates a possible association between triptolide/tripdiolide chronic intake and development of human herpesvirus 8-associated Kaposi sarcoma. Triptolide/tripdiolide could contribute to development of Kaposi sarcoma by reactivation of latent human herpesvirus 8, permitted by immunosuppression induced by triptolide.

PubMed

Clinical Manifestations of Kaposi Sarcoma Herpesvirus Lytic Activation: Multicentric CastlemanDisease (KSHV-MCD) KSHV Inflammatory Cytokine Syndrome

Clinical Manifestations of Kaposi Sarcoma Herpesvirus Lytic Activation: Multicentric CastlemanDisease (KSHV-MCD) and the KSHV Inflammatory Cytokine Syndrome.

2012

Polizzotto MN, Uldrick TS, Hu D, Yarchoan R.

Source

HIV/AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute Bethesda, MD, USA.

Abstract

Soon after the discovery of Kaposi sarcoma (KS)-associated herpesvirus (KSHV), it was appreciated that this virus was associated with most cases of multicentric Castleman disease (MCD) arising in patients infected with human immunodeficiency virus. It has subsequently been recognized that KSHV-MCD is a distinct entity from other forms of MCD. Like MCD that is unrelated to KSHV, the clinical presentation of KSHV-MCD is dominated by systemic inflammatory symptoms including fevers, cachexia, and laboratory abnormalities including cytopenias, hypoalbuminemia, hyponatremia, and elevated C-reactive protein. Pathologically KSHV-MCD is characterized by polyclonal, IgM-lambda restricted plasmacytoid cells in the intrafollicular areas of affected lymph nodes. A portion of these cells are infected with KSHV and a sizable subset of these cells express KSHV lytic genes including a viral homolog of interleukin-6 (vIL-6). Patients with KSHV-MCD generally have elevated KSHV viral loads in their peripheral blood. Production of vIL-6 and induction of human (h) IL-6 both contribute to symptoms, perhaps in combination with overproduction of IL-10 and other cytokines. Until recently, the prognosis of patients with KSHV-MCD was poor. Recent therapeutic advances targeting KSHV-infected B cells with the anti-CD20 monoclonal antibody rituximab and utilizing KSHV enzymes to target KSHV-infected cells have substantially improved patient outcomes. Recently another KSHV-associated condition, the KSHV inflammatory cytokine syndrome (KICS) has been described. Its clinical manifestations resemble those of KSHV-MCD but lymphadenopathy is not prominent and the pathologic nodal changes of KSHV-MCD are absent. Patients with KICS exhibit elevated KSHV viral loads and elevation of vIL-6, homolog of human interleukin-6 and IL-10 comparable to those seen in KSHV-MCD; the cellular origin of these is a matter of investigation. KICS may contribute to the inflammatory symptoms seen in some patients with severe KS or primary effusion lymphoma. Additional research is needed to better define the clinical spectrum of KICS and its relationship to KSHV-MCD. In additional, research is needed to better understand the pathogenesis and epidemiology of both KICS and KSHV-MCD, as well as the optimal therapy for both of these disorders.

Frontiers

CD8+ T cell immunity to Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus.

CD8+ T cell immunity to Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus.

Semin Cancer Biol. 2008 Nov 1

Hislop AD, Sabbah S.
CRUK Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; MRC Centre for Immune Regulation, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.

Gammaherpesviruses are agents which have evolved to persist within the lymphoid system and many have oncogenic potential; studying gammaherpesvirus infections therefore has the potential to reveal much about the workings of the immune system and the control over viral oncogenesis. The lymphocryptovirus Epstein-Barr virus (EBV) and the rhadinovirus Kaposi's sarcoma-associated herpesvirus (KSHV, also known as human herpesvirus 8) are the two human gammaherpesviruses. Analysis of the T cell response to EBV has guided understanding of immunity to infection and disease caused by this virus, as well as directed the development of vaccination and therapeutic interventions in EBV-associated disease. Less is known about the T cell response to KSHV and its exact role in controlling virus infection and disease. Here we discuss the CD8+ T cell response to these two gammaherpesviruses.

ScienceDirect