Introduction: Herpesviruses in hematology☆

Article Outline

 

This issue of Seminars in Hematology reviews herpesviruses that have been associated with hematological diseases, emphasizing pathogenesis, clinical manifestations, and treatment. Our contributors focus specifically on Epstein-Barr virus (EBV), Kaposi's sarcoma herpesvirus (KSHV, also called human herpesvirus-8 [HHV-8]), cytomegalovirus (CMV), herpesvirus-6 (HHV6), and herpesvirus-7 (HHV-7). Due in part to their recent identification and the generally benign nature of infection, information on HHV-6 and HHV-7 is still somewhat limited.

EBV and KSHV are structurally related gammaherpesviruses discovered in the context of distinct malignancies, endemic Burkitt lymphoma for EBV and Kaposi's sarcoma for KSHV. About forty years ago M.A. Epstein identified by electron microscopy EBV particles in cultured lymphoblasts from Burkitt lymphoma. KSHV is a much more recent discovery: in 1994, Y. Chang and P. Moore identified KSHV sequences in Kaposi's sarcoma cells by means of representational difference analysis. Through intense efforts by a number of investigators, much has been learned about EBV and KSHV gene expression in infected cells and tissues and their contribution to pathogenesis. Many disease manifestations are hematolological. Some fundamental questions remain the topic of intense investigation. For example, the role EBV plays in the pathogenesis of Burkitt lymphoma, the very tumor in which it was discovered, remains unclear.

One of the most interesting features of EBV, KSHV, and CMV biology is the complex relationship between infection and host immunity. This point is illustrated by the increased incidence of specific types of EBV- and KSHV-infected lymphoproliferative diseases/malignancies in immunocompromised individuals. EBV infects asymptomatically most adults worldwide, and establishes latency in a small proportion of B lymphocytes. However, in severely T-cell-immunodeficient organ transplant recipients, these latently infected cells can grow unbridled, much like primary cultures of EBV-infected B cells in vitro. Reducing immunosuppressive medications can effectively control the EBV-infected proliferating B cells. Kaposi's sarcoma, a multifocal angioproliferative disease composed of KSHV-infected spindle cells, is a very rare malignancy in the general population, yet it is the most common cancer in immunocompromised acquired immunodeficiency syndrome (AIDS) patients. CMV infects asymptomatically a large proportion of the adult population worldwide, but in post-transplant recipients and in AIDS patients can give rise to life-threatening, fulminant disease, which can be difficult to treat despite available antiviral drugs.

EBV, KSHV, and CMV share an ancient and intricate relationship with humans. As a result, these viruses seem to have captured from their host a number of genes that can serve useful functions. Both EBV and CMV encode a viral homologue of cellular interleukin-10 (IL-10) that is functionally active. Like their cellular counterpart, these viral IL-10s can inhibit T-cell immunity, promote B-cell growth, and inhibit major histocompatibility complex (MHC) class II expression. The BARF1 gene of EBV encodes a soluble colony-stimulating factor 1 (CSF-1) receptor that neutralizes CSF-1 activity, including the interferon alpha stimulatory function. Viral IL-6, an early lytic gene of KSHV with structural homology to cellular IL-6, can promote angiogenesis and hematopoiesis. Viral Survivin, a product of KSHV homologous to human Survivin, has antiapoptotic activities. The CMV gene UL146 encodes a functional IL-8-like chemokine that attracts cells expressing the chemokine receptor CXCR2 to the site of infection, a mechanism that enhances viral dissemination.

Another aspect of the complex relationship between EBV, KSHV, or CMV and their human host is the development of pathogen strategies to ensure persistent infection, including mechanisms to prevent death of the target cells, promote their proliferation, and evade immune surveillance. The EBV latency proteins EBNA2 and LMP-1 and the CMV gpUS3 gene product are examples. By binding to the cellular DNA-binding protein RBJk, the EBV nuclear protein EBNA2 acts as a functional homologue of Notch IC, promoting transcription of genes that are required for cell growth. One region of the C-terminal intracellular tail of LMP-1, identified as CTAR1, can bind to tumor necrosis factor (TNF) receptor-associated factors (TRAFs), resulting in TRAF signaling and downstream nuclear factor κB (NFκB) activation. NFκkB is a potent transcription factor that can promote expression of a variety of cytokines, including IL-6, which stimulates B-cell growth. A different region of the C-terminous of LMP-1, CTAR2, interacts with the TNF receptor death domain protein, TRADD, that normally transduces death-promoting signals but when bound to LMP-1 leads to cell proliferation. The human CMV gene product of gpUS3, an endoplasmic reticulum protein, can prevent transport of MHC class I molecules to the cell surface; this function is believed to reduce the effectiveness of cytotoxic cell clearance of virus-infected cells.

Despite having developed numerous strategies for spread in the humans and evasion of immune recognition, the most common outcome of infection with EBV, CMV, and KSHV in humans is the establishment of a symbiotic relationship with the host. After primary infection, these viruses establish some form of long-term latency in humans with only intermittent reactivation and shedding for horizontal transmission. All of these stages of virus infection commonly occur without apparent disease. Thus, the conditions described in this chapter should be considered as rare accidents. Over the last several years, we have gained considerable insight in the biochemical mechanisms of cell-virus interactions and the diseases associated with herpesvirus infection, and progress toward the development of therapeutic strategies is based on this knowledge. Much of this information resides in subspecialty journals. This issue of Seminars contains reviews by experts designed to provide an update on herpesviruses in hematology directed at the general reader with an emphasis on the new and the clinical, but including a strong scientific background.