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Arvin A, Campadelli-Fiume G, Mocarski E, et al., editors. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press; 2007.

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Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis.

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Chapter 22Introduction to the human γ-herpesviruses

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This chapter will provide a brief background into the γ-herpesviruses family in comparison to other members of the herpesvirus family; but the primary focus of this chapter will be to recount the discovery of the two human γ-herpesviruses (EBV and KSHV) and the diseases associated with infection of each virus, a brief introduction into their life cycles, and finally a description of the genome characteristics of the viruses including a description of their respective genomes. In many ways, the discovery and association with human diseases for both EBV and KSHV have many parallels despite almost three decades separating their discoveries and association with human disease.

The γ-herpesvirus family

The γ-herpesviruses are a subfamily of herpesviruses that were first distinguished by their cellular tropism for lymphocytes. Subsequent molecular phylogenetic analyses have confirmed the close relationship among these viruses that is distinct from the α- and β-herpesviruses subfamilies (Fig. 22.1). Gammaherpesvirinae is currently divided into two genera, Lymphocryptoviridae which includes human Epstein–Barr virus (EBV or HHV 4) and Rhadinoviridae, which includes human Kaposi’s sarcoma-associated herpesvirus (KSHV or HHV 8). Recent studies suggest that primate rhadinoviruses can be further subdivided in KSHV -like viruses, a second closely related but distinct lineage of Old World primate viruses related to the rhesus rhadinovirus (RRV), and the New World monkey rhadinoviruses represented by herpesvirus saimiri (HVS). A more detailed analysis of the non-human γ-herpesviruses will be discussed in Chapters 60 and 60.

Fig. 22.1. Phylogenetic tree for selected herpesviruses.

Fig. 22.1

Phylogenetic tree for selected herpesviruses. Phylogenetic trees are based on comparison of aligned amino acid sequences between herpesviruses for the MCP gene. The comparison of MCP sequences was obtained by the NJ method and is shown in unrooted form, (more...)

Although the best-studied members of the γ-herpesviruses are EBV and KSHV, γ-herpesviruses are parasites of a broad range of mammals from mice (murine herpesvirus-68 and related viruses) to cows and horses (bovine herpesvirus 4 and equine herpesvirus 2), as well as primates. Surprisingly, γ-herpesviruses of lower mammals most closely resemble the rhadinoviruses, and exhibit extensive molecular piracy of host regulatory genes that is not found in EBV and related viruses. Interestingly, the lymphocryptoviruses have been found only in primates and humans. The γ-herpesviruses share a similar genomic structure that the 172 kilobase pair, linear double-stranded DNA genome of the B95–8 EBV strain serves as the prototype since it was the first γ-herpesvirus that was sequenced (Baer et al., 1984). The large central region of the genome contains most of the coding capacity for the viruses, including blocks of highly conserved genes that are shared among the herpesviruses (Fig. 22.2). The ends of the molecule are capped by variable numbers of direct repeat sequences that are the sites for genome circularization during latency. Unlike the α-herpesviruses (Chapter 10), the γ-herpesviruses do not undergo genomic isomerization and only linearize and recircularize in their terminal repeat regions, although the numbers of terminal repeats can be highly variable.

Fig. 22.2. Colinearity of the genetic maps of KSHV (top) and EBV (bottom).

Fig. 22.2

Colinearity of the genetic maps of KSHV (top) and EBV (bottom). Schematic representation of the genomes of KSHV and EBV were drawn to scale based on the sequences by Russo et al. (PNAS 93, 14862–14867, 1996; Genbank acc. no. U75698) and the inverted (more...)

The γ-herpesviruses also share a number of characteristics in common with the α- and β-herpesviruses, particularly related to lytic viral replication. During lytic replication, the γ-herpesviruses genome is packaged as a linear molecule in a proteinaceous capsid, which is then enveloped by a lipid bilayer prior to release from the cell. This process starts when viral transactivators initiate viral genome-wide transcription through a series of orderly transcriptional cascades. Different classes of viral genes (immediate–early, early and late) are transcribed resulting in the production of infectious virions. As with other herpesviruses, γ-herpesviruses lytic replication is thought generally to cause cell death. While specific mechanisms for lytic replication differ between the herpesviruses, and even among the γ-herpesviruses, they all broadly share similar capsid structures and have similar overall mechanisms for lytic replication. As would be expected, genes involved in lytic replication and viral capsid production tend to be highly conserved across the herpesvirus subfamilies, including the γ-herpesviruses.

The γ-herpesviruses differ the most dramatically from each other and from other herpesviruses during the latent portion of their lifecycle. Unlike the other human herpesviruses, both EBV and KSHV latency can be established and manipulated in vitro, providing an important experimental system that is unavailable for other viruses. Latency occurs after infection of a cell and transport of the capsid to the nucleus where the genome is released. The viral genome, still a linear DNA fragment, then circularizes by ligation of terminal repeat sequences and replicates as an episome using the host cell replication machinery.

A key feature of the γ-herpesviruses is their common capacity to induce lymphoproliferation and cancers. Tumors caused by EBV and KSHV include lymphoproliferative diseases and lymphomas, but also include tumors from other tissue-types, such as smooth muscle cells and endothelial cell origin. In some cases, tumorigenesis occurs when viruses cross species such as bovine infection by the wildebeest γ-herpesviruses, alcelaphine herpesvirus 1, in Africa (Ensser et al., 1997). In other cases, tumorigenesis is a rare occurrence among infected individuals, except when the host is specifically susceptible through immunosuppression or through a rare familial mutation altering normal immune function.

EBV was the first human tumor virus discovered and has been a rich source of information for tumor biologists as well as a tool for immortalizing cell lines for use as reagents. As shown by the Henles in 1967, EBV has the unusual property of immortalizing primary B lymphocytes in culture (Henle et al., 1967). Continuous cell lines that result from this immortalization are termed lymphoblastoid cell lines (LCLs) reflecting their activated phenotype. These LCLs contain EBV episomes and express a very limited number of viral genes and have served as an important model of EBV latent infection and transformation as will be further discussed in Chapter 24. These latently infected cell lines, as shown in 1978 by zur Hausen and colleagues can be induced to lytic replication by treatment with phorbol esters (zur Hausen et al., 1978). Interestingly, similar treatment of cell lines harboring KSHV causes induction of lytic replication (Arvanitakis et al., 1996; Renne et al., 1996).

KSHV, more recently discovered, provides a unique tumor virus model since it has incorporated cellular proto-oncogenes and serves as a rosetta stone between cancer biology and tumor virology. The natural lifecycles of EBV and KSHV are well studied and experimentally tractable allowing for the careful examination of oncogenes from these viruses not only in terms of their capacity to induce cell transformation but also in terms of their roles in the natural viral life cycle.

The discovery of Epstein–Barr virus (EBV)

Although there was considerable evidence to indicate the role of viruses in human cancers from animal studies dating from the early 1900s, it was not until the identification of Burkitt’s lymphoma and the subsequent identification of EBV in this unusual tumor that a clear role of viruses in human cancers became apparent. The first key to the puzzle of a human virus being associated with a human tumor resulted from the interest of Denis Burkitt with a malignancy in children in Africa.

Denis Burkitt was born in 1911 and lived in Lawnkilla near Enniskillen, County Fermanagh, Ireland. He received his medical training at Trinity College in Dublin with his clinical training at Adelaide Hospital. Following graduation and after working in hospitals in his native Ireland and military service as army surgeon in the Royal Army Medical Corps, Burkitt embarked on a career of medical service in Africa due in part to his strong religious convictions and interest in service in the third world. In 1957, after being in Kampala, Uganda, for 10 years, he was asked by Hugh Trowell, a colleague in Kampala, to see a young boy with swellings on both sides of his upper and lower jaws that proved to be a lymphoma. The tumor was a very common cancer in African children, was fast growing causing grotesque disfigurement, and was fatal upon metastasis to other parts of the body.

Burkitt’s fascination and interest in the tumor led him to carefully examine hospital records and to send out a questionnaire to government and mission hospitals throughout Africa. He also embarked on what he would call his long safari to document the incidence of this lymphoma. From this trip, which took 10 weeks, covered 10 thousand miles, journeyed through 12 countries, and stopped at 57 hospitals; Burkitt found a definite pattern of distribution with the lymphoma confined to a region 10 degrees north and 10 degrees south of the equator following closely the pattern of distribution of mosquito borne diseases such as malaria and yellow fever. These initial results were published in the British Journal of Surgery in 1958 (Burkitt, 1958). But it was not until 1961 after publication of a more detailed version in Cancer with a pathologist Greg O’Conor (Burkitt and O’Conor, 1961) and an invitation to give a lecture at Middlesex Hospital in London in March of 1961 that allowed the next step in the identification of EBV to fall into place.

In the audience of Burkitt’s talk at Middlesex Hospital was Anthony Epstein who immediately developed an interest in the Burkitt’s tumor. Epstein, who had worked on the Rous sarcoma virus, had developed an interest in the role of viruses in cancer and he was fascinated with Burkitt’s description of his findings. Rous sarcoma virus was shown in 1911 by Peyton Rous at the Rockefeller Institute in New York to be responsible for a sarcoma that was transmissible in chickens. Epstein and Burkitt immediately began to collaborate. Biopsies were flown from Kampala to Epstein’s laboratory in London, but it was not until 1963 after Yvonne Barr and Bert Achong joined the hunt that herpesvirus-like particles were observed in February 1964 from a cell line established from a biopsy delivered from Africa early in December of 1963 (Epstein et al., 1964). Interestingly, both Achong and Barr were graduates of schools in Ireland. Achong graduated from University College Dublin and Yvonne Barr was a graduate of Trinity College Dublin.

Human disease associated with EBV infection

Considerable interest has focused on EBV since its discovery and its link with Burkitt’s lymphoma. Along with KSHV, as we will learn also in this chapter, EBV is the only other herpesvirus with an etiological role in human malignancies. As described above, EBV is a causative agent in endemic Burkitt’s lymphoma, but since the link of EBV with this lymphoma, EBV has also been shown to be important for a large number of additional diseases in humans.

Shortly after the description of EBV association with Burkitt’s lymphoma, the Henles, a husband and wife team at the Children’s Hospital of Philadelphia obtained a set of cell cultures from Epstein. Werner and Gertrude Henle were both born and educated in Germany. Werner emigrated to the United States in 1936 finding an instructorship position at the University of Pennsylvania. Werner’s grandfather, Jacob Henle, was of Jewish descent, making his further training and livelihood in question because of the increased power of the Nazi regime in Germany and the approaching war. It had become “increasingly clear” to Werner that he could “not stay in Germany and pursue a career to his liking.” In 1937, Gertrude Szpingier, who was Werner’s fiancée, joined Werner in Philadelphia. They had met at the University of Heidelberg and were married the day after Gertrude’s arrival in the United States. They spent their entire careers at the University of Pennsylvania making not only important discoveries in regard to EBV, but also other aspects of virology, immunology, and viral oncology.

With the cultures in hand from Epstein, the Henles began to explore the presence of antibodies directed against the new virus. By analyzing the immune response, Gertrude and Werner demonstrated that the EBV was widespread in the human population (Henle and Henle 1966; Henle et al., 1969). As expected, they found antibodies to EBV in children with Burkitt’s lymphoma, but also in the serum of healthy African children. Also, as may have been expected, the antibody titers in Burkitt’s lymphoma patients were much higher that in healthy children. More surprising, was the finding that antibodies were found in most serums from children tested all over the world indicating that the virus was ubiquitous within the human population. Burkitt’s lymphoma cell lines in culture were also used at this time by Lloyd Old and his colleagues at the Memorial Sloan–Kettering Cancer Center in New York to make the initial connection of EBV infection and nasopharyngeal carcinoma (Old et al., 1966).

Because antibodies to EBV were so ubiquitious, the Henles suspected that infections with EBV were common and were generally self-limited in nature. Interestingly, this has been a common observation in regard to most of the herpesviruses that were subsequently discovered. At the time of the discovery of EBV, only three other human herpesviruses were known. These were herpes simplex virus (HSV), varicella-zoster virus (VZV), and cytomegalovirus (CMV). All of these viruses caused overt symptoms as in the case for HSV and VZV, or were associated with serious congenital defects. As will be discussed in other chapters and this chapter, HHV 6, HHV 7, and KSHV cause little disease in immune competent individuals. It is only when the immune host immune system is compromised that overt symptoms typically appear with infection of these viruses.

As is the case for many discoveries, serendipity led to the discovery of the association of EBV with infectious mononucleosis. Late in 1967, a technician working in the Henle laboratory developed classical symptoms of infectious mononucleosis (Henle et al., 1968). Prior to her symptoms, she had shown no antibodies to EBV, but with her symptoms, antibodies appeared to EBV. As will be reviewed in the later chapters, we will learn that, along with the association of EBV with Burkitt’s lymphoma, NPC, and infectious mononucleosis, EBV has now been found to be involved in a much wider range of human disease. It is generally accepted that EBV is involved with several other malignancies of lymphocyte origin such as some types of Hodgkin’s lymphoma, and epithelial origin such as gastric carcinoma. Table 22.1 contains a list of diseases with known EBV etiology. Each of these disease associations will be expanded in later chapters and specific references can be found in these chapters. EBV is also a factor in a variety of other human malignancies including some T and NK cell lymphomas.

Table 22.1. EBV associated pathologies in the human host.

Table 22.1

EBV associated pathologies in the human host.

The association of EBV with other diseases, such as breast carcinoma and hepatocellular carcinoma, remain controversial and will likely only be resolved in the coming years with additional research. In immunosuppressed patients, EBV causes a variety of proliferative disorders including oral hairy leukoplakia in AIDS patients, immunoblastic lymphomas, and an unusual tumor of muscle origin in children with AIDS or who are under immune suppression for liver transplantation. In young boys with X-linked immunodefiencies, EBV causes severe mononucleosis that results in death.

Evidence is accumulating that the EBV may also be associated with immune mediated diseases. In particular, there is a variety of auto-immune diseases that appear to have an infectious agent as a cofactor such as multiple sclerosis, rheumatoid arthritis, and diabetes. For each of these autoimmune diseases, it has been suggested that EBV may have an involvement in causing deregulation of the normal immune response to self-antigens. But, since EBV is so ubiquitous, many of these studies are also controversial. The linking of EBV infection to autoimmune disease and controversial malignancies such as breast carcinoma and hepatocellular carcinoma may await the development of an effective vaccine against EBV which will be discussed in Chapter 72. By preventing primary infection, an effective vaccine would offer convincing proof of a disease association due to absence of a particular disease or malignancy in those vaccinated for EBV. This may allow the true appreciation of the wide variety of disease associated with EBV infection in humans.

EBV life cycle

Infection with EBV usually occurs early in childhood, resulting in an asymptomatic infection. The virus is spread through saliva. If primary infection occurs later, B-cell proliferation and the resulting immune response results in infectious mononucleosis. After primary infection, most individuals will harbor the virus for the remainder of their life, and carriers develop cellular immunity against a variety of both lytic and latency associated proteins that will be more discussed later in this chapter as well as in Chapter 51. By adulthood, the majority of the human population (upwards of 90%) is infected with EBV. Periodically, virus is shed from latently infected individuals by the induction of lytic replication in B lymphocytes. The true site of latent infection has not been determined, but the virus likely resides in B lymphocytes. Recent studies have shown that EBV can be detected in circulating peripheral blood lymphocytes in carriers of EBV latent infections by PCR (both for viral DNA and viral mRNA) (Tierney et al., 1994; Chen et al., 1995; Babcock et al., 1999; Qu et al., 2000) and virus isolation and outgrowth of immortalized cell lines by culturing peripheral lymphocytes (Yao et al., 1985). It has not been determined if this is the true site of latency. Other potential sites of EBV latency may include bone marrow, lymph nodes, or other lymphoid organs.

Early experiments suggested that latency is not maintained by constant re-infection of circulating B-lymphocytes as evidenced in patients treated with acyclovir (Yao et al., 1989). Acyclovir, a nucleoside analogue that can inhibit lytic replication in the oral epithelium had no effect on the number of B-cells in the peripheral blood population that harbor the virus. More recent experiments have shown that viral gene expression may be greater than may have previously been thought in lymphoid organs such as the tonsil suggesting that the virus may manipulate normal B-cell development and survival to insure continued latency by the expansion of infected cells without lytic replication (Miyashita et al., 1997; Babcock et al., 1998, 2000; Babcock and Thorley-Lawson, 2000; Joseph et al., 2000a,b; Thorley-Lawson, 2001; Hochberg et al., 2004a,b). This will be more fully discussed in later chapters.

Further evidence of the hematopoetic site of EBV latency comes from engraftment of bone marrow cells that can result in the loss of the resident virus or the appearance of a new virus strain from donor lymphocytes (Gratama et al., 1989). Lytic replication is presumed to occur when EBV infected B lymphocytes traffic through and transmit infection to oral epithelium providing a source for infection of other individuals. Interestingly, recent studies have suggested different virus strains are present within different compartments in humans with EBV latent infection such as peripheral blood and the oral cavity suggesting that epithelial infection may be more important than previously thought (Sitki-Green et al., 2003). Understanding the complex interplay in EBV latency in the human host and the importance of viral gene expression requires the careful analysis of EBV gene function which will be the topic of other chapters.

The discovery of Kaposi’s sarcoma-associated herpesvirus (KSHV)

The discovery of KSHV or human herpesvirus 8 (HHV8), has many parallels with the discovery of Epstein–Barr virus. Like Dennis Burkitt, Patrick Moore and Yuan Chang, were intrigued by the appearance of a new cancer in the United States, but rather than appearing in very young children, the disorder was appearing in young healthy gay men (Jaffe et al., 1983). This disorder was Kaposi’s sarcoma (KS). KS was originally described as idiopathic purplish pigmented sarcoma of the skin by Moriz Kaposi in 1872 (Kaposi, 1872). Kaposi, born Moriz Kohn in Kaposvar, Hungary, obtained his MD in Vienna in 1861 and worked with Ferdinand Hebra, the founder of a renowned School of Viennese Dermatology. He would later become Hebra’s son-in-law in 1869 and his successor in 1881. Also in 1869, Kaposi wrote the initial description of lupus erythematosus with a more comprehensive description published in 1872. He also described xeroderma pigmentosum. In 1871, two years after converting from Judaism to Roman Catholic and marrying Hebra’s daughter, he changed his name to reflect his birthplace. In contrast to the frequent surname Kohn, Kaposi was certainly unique in Vienna, thus avoiding being mixed-up with others. In addition, this name change may have guarded against the harsh anti-semitism during the rule of Emperor Franz-Josef. Like his more comprehensive description of lupus erythematosus, it was also in 1872 that Kaposi published his description of the sarcoma that now bears his name. KS was a relatively rare, indolent, pigmented growth typically found on the skin of elderly men. Initially, Kaposi reported on the clinical features of six cases, including one of a young boy, but the remaining cases were all in men over 40 years of age. He reported that the disease was incurable and often resulted in death within two years after the disease appeared. In the 1960s, before the AIDS epidemic, it was realized that KS was not as rare as initially thought. The incidence in equatorial tropical Africa or sub-Sarahan African is much greater as will be more fully discussed below.

Following the outbreak of AIDS in the 1980s, in which there was a dramatic increase of KS in AIDS patients, there was considerable interest in the further study of this unusual malignancy and in particular the association of KS with infection with a human pathogen. Like Burkitt’s lymphoma, a role for a virus was suspected in KS lesions long before the onset of HIV infection and the resulting AIDS epidemic. As early as 1972, herpesvirus-like particles were found in electron microscopic analysis of KS biopsies (Giraldo et al., 1972). This virus was determined to be cytomegalovirus (CMV), a herpesvirus that is ubiquitous in the human population. By the early 1990s, a number of other pathogens had also been found in KS lesions by a variety of investigators. Typically, these agents were not found in all the lesions and in many cases they were ubiquitous agents in the human population and were subsequently dismissed as having a role in KS. Like Burkitt’s lymphoma, there was epidemiological data that suggested the role of an infectious agent in the development of KSHV. But before the identification of KSHV, it was thought that HIV may be the critical factor in the development of AIDS -associated KS. However, the uneven distribution of KS among different transmission groups for the human immunodeficiency virus (HIV) resulted in the hypothesis that an environmental factor or a transmissible agent other than HIV was involved in KS pathogenesis (Beral et al., 1990). Most notably, whereas more than 20% of homosexual and bisexual AIDS patients developed KS, only 1% of age- and sex-matched men with hemophilia suffered from this uncommon tumor, suggesting transmission of a KS -related virus by sexual practice.

The first real break that led to the discovery that a herpesvirus was linked to KS came in 1993 when Yuan Chang moved to Columbia University to take up a position in neuropathology. Chang received her medical degree from the University of Utah College of Medicine. Patrick Moore married Yuan Chang and in 1989 he left his job at the Centers for Disease Control to follow Chang to New York. Moore received a MS from Stanford in 1980, his MD from the University of Utah School of Medicine in 1985, and his MPH from the University of California, Berkeley in 1990. Once in New York, Moore was unable to find an appropriate academic position, so he joined the New York City Health Department. Both Moore and Chang were interested in identifying new pathogens without in vitro culture since this was a question that Moore was interested in from his work at the Centers for Disease Control. A recent publication from Michael Wiglers’ laboratory at Cold Spring Harbor detailed a new technique called representational difference analysis (RDA). This technique, which was developed by the Lisitsyns, used PCR to identify DNA sequences present in one sample but not a control sample. On the surface, this looked ideal for the identification of unique infectious agents. The paper describing this technique was published in Science (Lisitsyn et al., 1993). It was not used to detect unique pathogen, but only the feasibility of using this technique was demonstrated using lambda or adenovirus DNA. Barry Miller, a colleague of Patrick Moore at the Centers for Disease Control, suggested that Moore and Chang apply this technique in their pathogen discovery.

With a single KSHV lesion and control tissue, the husband and wife team began to perform RDA. The initial experiments were performed by Chang and Melissa Pessin. Pessin was a pathology resident on a research rotation at Columbia. Moore helped in the evenings after finishing his duties at the New York City Health Department. The initial amplifications resulted in four prominent bands. Two KS lesions were positive for two of the four bands by Southern hybridization, but surprisingly, a control tissue from an AIDS patient was also positive. The control tissue was from an unusual lymphoma found in AIDS patients. This lymphoma, characterized by pleural, pericardial, or peritoneal lymphomatous effusions, is referred to as primary effusion lymphoma (PEL) or body-cavity based lymphoma and would also be shown to be positive for the new herpesvirus that Chang and Moore identified as will be detailed later.

Testing a larger panel tissue, Moore and Chang found that virtually all of the KS lesions were positive while none of the controls showed the same number of positives. From sequencing the RDA products, they developed internal PCR primers for one of the sequences that allowed a simple PCR based screen for analysis of additional tissues. Surprisingly, when the initial sequences were compared to sequences available in the current databases, no homologous sequences were identified. This suggested an unknown pathogen. Moore quit the Health Department in January 1994 so that he could devote his efforts full-time to the project at Columbia. Chang made an important contact working in the spring of 1994 with Frank Lee and Janice Culpepper at the DNAX Institute for molecular biology. Lee, working with newly developed BLAST sequence alignment algorithms, was able to show that DNA fragments isolated by RDA from KS lesions unambiguously belonged to a new herpesvirus, similar to but distinct from known herpesviruses. With this data in hand, a paper was submitted to Science and was accepted for publication in December of 1994, identifying a new herpesvirus (Chang et al., 1994). Both Moore and Chang have recently moved to the University of Pittsburgh School of Medicine, where Chang is a Professor of Pathology and Moore is a Professor of Molecular Genetics and Biochemistry and Director of the Molecular Virology Program at the University of Pittsburgh Cancer Institute.

KSHV life cycle

Like EBV, KSHV requires intimate contact for transmission. At least in regions endemic for KS, all evidence points to similar modes of transmission in young children as has been described for EBV (Mayama et al., 1998; Martro et al., 2004). Primary infection likely occurs from contact via saliva with parents, siblings, playmates, and close relatives at a very early age. Similarly, in adult populations close intimate contact is also required. Interestingly, in comparison to EBV the infection rates of KSHV within the human population can vary dramatically throughout the world population based on serology. In endemic regions such as Africa, infections rates are well over 50%, whereas in Northern Europe and the United States, infection rates range from 1–6% (Gao et al., 1996; Kedes et al., 1996; Simpson et al., 1996). Southern Europe, which like Africa, has a higher incidence of KS, also has a higher rate ranging from 10%–30% when compared to infection rates in the United States and Northern Europe (Schatz et al., 2001). As might be expected, infection rates measured by serology are higher in homosexual men than in the general population in western countries, ranging from 20%–40% in homosexual men not suffering from KS (Martin et al., 1998). In immunocompromised KSHV infected individuals, a wide assortment of cells and tissues has been shown to harbor KSHV. Most frequently, peripheral B cells have been reported to carry the KSHV genome (Ambroziak et al., 1995). But T-cells, monocytes, and endothelial cells have also been found positive for KSHV DNA (Henry et al., 1999; Blackbourn et al., 2000). In contrast, the site of latency in immunocompetent individuals is essentially unknown. Difficulties in detecting viral DNA in seropositive, healthy individuals may reflect a low frequency of spontaneous KSHV reactivation, which would in turn result in the scarceness of KSHV positive cells and relatively low KSHV transmission rates at least in North America, Northern Europe and most parts of Asia. As a consequence, sites of persistence and the overall strategy of KSHV latency in the human host have been difficult to determine as of this date. The supposedly low rate of spontaneous reactivation in immunocompetent individuals is also reflected by low and declining antibody titers (Martro et al., 2004). The latter has made it difficult initially to estimate the seroprevalence of KSHV in the general population (Pellett et al., 2003), as will be detailed in Chapter 54.

Human disease associated with KSHV infection

Symptoms related to primary infection with KSHV have only recently been described (Andreoni et al., 2002). Like EBV, it would appear that symptoms in immunocompetent individuals are very modest with primary infection being largely asymptomatic. In children, this primary infection may be associated with a febrile maculopapular skin rash (Andreoni et al., 2002). Reports have indicated that primary infection in adults undergoing immune suppression for organ transplantation have experienced bone marrow failure, splenomegaly, and fever (Luppi et al., 2002). There is also evidence that KSHV may be transmitted by solid organ transplants, eventually resulting in the development of rapidly progressing KS (Barozzi et al., 2003; Marcelin et al., 2004). However, at present it is not clear whether screening of organ donors for KSHV infection is beneficial.

Despite the only recent identification of KSHV, remarkable progress has been made in the identification of pathological consequences of infection with KSHV. Along with EBV, as described above, KSHV is also associated with proliferative disorders in both immune competent and immune deficient humans. In endemic regions of Africa, KS is a common debilitating cancer among men, women, and children. Following the establishment of this link, KSHV has also been shown to be important for a number of other diseases in the human population as will be described.

Classical KS, as originally identified by Kaposi, was typically seen in elderly Mediterranean patients, was indolent in nature, and affected the skin of the lower limbs. In endemic KSHV infection in Africa, before the HIV epidemic hit, KSHV infection presents as four distinct clinical syndromes: relatively benign, nodular cutaneous disease which is very similar to classical KS, aggressive cutaneous disease which invades both bone and localized soft tissue, florid visceral and mucocutaneous disease, and finally lymphadenopathic disease that can rapidly disseminate to lymph nodes and visceral organs (quite often in the absence of cutaneous disease). The final syndrome typically occurs in children. KS associated with immune suppression either from HIV infection or organ transplantation commonly presents multifocally and symmetrically and may arise quickly. These lesions will often undergo spontaneous remission with improving immune status.

As discussed earlier, there were early indications that another proliferative disorder observed in HIV patients might also be related to KSHV infection. Early work by Chang and Moore found that an unusual lymphoma in patients with AIDS was also positive for KSHV DNA (Chang et al., 1994). The lymphoma was confined primarily to body cavities and grows as an effusion. Hence the names primary effusion lymphoma (PEL) or body-cavity based lymphoma. Daniel Knowles and Ethel Ceserman working with Moore and Chang established that these tumors are also uniformly positive for KSHV (Cesarman et al., 1995). Interestingly, the vast majority of these tumors are also positive for EBV.

The final disease in human associated with KSHV infection is multicentric Castleman’s disease (MCD). MCD was first described by Castleman in 1956 and is an unusual lymphoproliferative disorder that is characterized by lymphadenopathy, fever, and splenic infiltration (Castleman et al., 1956). KSHV is present in nearly all the cases of MCD in AIDS patients as originally shown by Soulier and colleagues in 1995 and about half of the cases in HIV -negative patients (Soulier et al., 1995). MCD is considered to be a semi-malignant lymphoproliferative disorder, associated with IL -6 hyperproduction and inflammatory symptoms. In the context of MCS, however, a highly aggressive plasmablastic non-Hodgkin-lymphoma may arise which is also KSHV positive and likely to have arisen from monoclonal “microlymphomas” detectable in some MCD lesions (Dupin et al., 2000).

Finally, there have been reports of the potential association of KSHV infection with sarcoidosis (Di Alberti et al., 1997) and multiple myeloma (Rettig et al., 1997), but as is the case with EBV association with liver and breast cancer, the linkage of KSHV infection with these two pathologies requires additional confirmation before a definitive link is established. In 2003, C. D. Cool et al. detected DNA and antigen of KSHV in lung tissues of 10 out of 16 patients with severe primary pulmonary hypertension (Cool et al., 2003). It is fascinating to note that, like MCD, PEL, and KS, primary pulmonary hypertension is frequently associated with HIV -1 infection. However, several follow-up studies were not able to confirm this intriguing finding (Henke-Gendo et al., 2004 and reviewed in D. Rimar et al., July 2006). But C. D. Cool and coworkers argue, that in contrast to their initial work most follow-up studies were based on serological assays. In fact, only two of the studies used DNA-PCR and/or histochemistry Katano et al., 2005; Daibata et al., 2004), and these were performed on patients from Japan, were KSHV prevalence is very low. Thus, further work is needed before a link between PPH and KSHV infection can be considered shown.

Phylogenetic relationship between EBV, KSHV, and non-human γ-herpesvirus genomes

The γ-herpesviruses are split into two subfamilies: the γ1-herpesviruses and the γ2-herpesviruses. The two human γ-herpesviruses include the recently identified KSHV, and EBV, which are distinguished by their latent infection of lymphoblastoid cell lines either of T- or B-cell origin. EBV is the only human member of the genus γ1-herpesvirus also termed lymphocryptovirus. A number of related viruses have been identified that infect both New World and Old World primates (Wang, 2001; Wang et al., 2001). These viruses serve as important models to investigate the pathogenesis of the lymphocryptoviruses in vivo (see Chapters 60 and 61). KSHV is a member of the γ2-herpesviruses or rhadinoviridae and like EBV has important related viruses that infect New and Old World primates. Herpesvirus saimiri (HVS), which infects squirrel monkeys, has been well studied and also provides an important model of KSHV in vivo pathogenesis (Fickenscher and Fleckenstein, 2001). Following the discovery of KSHV in man, several studies were undertaken to detect additional Old-World primate rhadinoviruses. By searching for antibodies cross-reactive with KSHV, the group of Ronald Desrosiers at the New England Primate Research Centre isolated the rhesus monkey rhadinovirus (RRV) (Desrosiers et al., 1997). The complete genomic sequence of RRV clearly showed that this virus is more closely related to KSHV than herpesvirus saimiri (Searles et al., 1999). In particular, most genes not conserved between KSHV and herpesvirus saimiri, the so-called “K” genes, do have homologues in RRV. In contrast to HHV -8, RRV can be readily propagated in cell culture. While RRV was discovered at the East Coast, Timothy M. Rose and Marnix Bosch were sleepless in Seattle. They studied tissue specimens from rhesus monkeys suffering from retroperitoneal fibromatosis (RF) at the Washington Regional Primate Research Centre. RF has been identified as an infrequent disease syndrome occurring in immunosuppressed macaques (Giddens et al., 1985). RF lesions somewhat resemble KS: they consist of an aggressively proliferating fibrous tissue with a high degree of vascularization, and transmission studies indicated that an infectious agent may be involved in RF pathogenesis. By using a degenerated PCR technique, fragments of a herpesvirus DNA polymerase gene were identified in RF tissues from two macaque species, Macaca nemestrina and Macaca mulatta (Rose et al., 1997). Sequence comparisons indicated that, at least the DNA polymerase genes of these two novel rhadinoviruses, tentatively termed RFHVMm and RFHVM n, are more closely related to KSHV than the DNA polymerase genes of RRV. In addition, the LANA gene of RVHV mn is closely related to KSHV in structure and sequence. A role of RFHVMn in the pathogenesis of RF is suggested by the finding that RF spindle cells are highly positive for RFHVMn LANA (Burnside et al., 2006). However, attempts to isolate these viruses on cultured cells have not been successful so far. Several rhadinoviruses have been discovered since then in various Old World primates, including chimpanzees, gorillas and orang-utans. Phylogenetic analysis clearly showed that these Old Word primate rhadinoviruses form two clades. KSHV is the prototype of one clade, and RRV the prototype of the second clade. The thrilling point here is: most Old World primate species seem to harbor representatives of both clades. The search for a second rhadinovirus in man has not been successful to date, however.

Human γ-herpesviruses genomes

At least two EBV types have been identified in human populations and these were formerly designated EBV type A and type B (Zimber et al., 1986) but have recently been designated EBV -1 and EBV -2 to parallel the HSV -1 and HSV -2 nomenclature. The majority of EBV isolates in western communities are type 1, while type 2 EBV isolates appear to be largely restricted to equatorial Africa and Papua New Guinea. Unlike HSV -1 and HSV -2, there is extensive nucleotide homology and restriction endonuclease site conservation throughout most of the EBV -1 and EBV -2 genomes. However, there are important differences in the sequence of key EBV genes such as EBNA 2 and the EBNA 3 family of genes (Dambaugh et al., 1984; Sample et al., 1990). But, overall, the two types of EBV are considerably more closely related to each other than are HSV -1 and HSV -2 (Lees et al., 1993). Related to the differences in key EBV genes, the EBV -1 strains transform lymphocytes more readily and to faster growing cell lines than do EBV -2 strains (Rickinson et al., 1987).

EBV has a linear double-stranded genome of approximately 172 kilobase pairs (kb) and has a base composition of 59% guanine plus cytosine. It was the first large DNA virus whose complete sequence was determined (Baer et al., 1984). Subsequent to the sequencing of the EBV genome, the VZV, HSV, CMV, HHV 6, and KSHV genomes were cloned and sequenced. The EBV genome sequenced, designated B95–8, was from an EBV -infected marmoset cell line partially permissive for lytic replication (Miller et al., 1972). Upon further analysis, it was determined that this virus isolate contained a deletion of approximately 12 kb relative to other EBV strains. Sequence analysis of Raji EBV strain revealed the 12 kb region deleted from B95–8 contained three potential open reading frames (Parker et al., 1990). The sequence analysis to date predicts around 85 to 95 open reading frames (Table 22.3, Fig. 22.2). The nomenclature for each identified gene in the sequence is based on the BamHI fragment in which the reading begins. This is followed by an “L” or an “R,” depending on the whether the reading frame is leftward or rightward. The reading frames in each BamHI fragment are then numbered. As is apparent from the Table 22.2, many of the reading frames also have another name based on the prior identification of the gene product or homology to well described genes or gene products described in other herpesviruses.

Table 22.3. EBV genes.

Table 22.3

EBV genes.

Table 22.2. KSHV associated pathologies in the human host.

Table 22.2

KSHV associated pathologies in the human host.

The KSHV genome is a linear, double-stranded DNA of approximately 160 kbp and has the overall structure typical for rhadinoviruses (Fig. 22.2) (Russo et al., 1996). A complete rhadinovirus genome is usually termed M genome, as it is of intermediate density (M-DNA). The γ2-herpesviruses were termed “rhadino” viruses utilizing the ancient greek word for fragile, because this M-DNA tends to split into two fractions of DNA molecules with highly different density, the L-DNA containing genes (low density, low G+C content) and the terminal repetitive H-DNA (high density, high G+C content). The latter is, as far as known until today, without coding capacity. The L-DNA contains at least 89 open reading frames, 67 of which have homologues in the closely related γ2-herpesvirus prototype herpesvirus saimiri. The overall amino acid sequence identity of these 67 KSHV reading frames to homologues identified in herpesvirus saimiri ranges from 22.4 to 66% (average: 42%). Conserved genes are usually found in a comparable genomic position and orientation. Thus, KSHV genes that share homology with herpesvirus saimiri are numbered from left to right according to their position on the herpesvirus saimiri genome. Open reading frames which do not share recognizable amino acid homology with genes in herpesvirus saimiri are numbered with the prefix “K” (Table 22.4). Until today, 19 genes have been identified which are not clearly homologous to genes identified in herpesvirus saimiri (K1 – K15, K4.1, K4.2, K8.1, K10.5). Frequently, these “K” genes are strikingly homologous to known cellular genes. They code for proteins interfering with the immune system, for enzymes of the nucleotide metabolism, and for putative regulators of cell growth (Table 22.4).

Table 22.4. KHSV genes.

Table 22.4

KHSV genes.

Despite enormous differences in base composition, it is apparent that herpesvirus genomes have many open reading frames in common. Many products of EBV genes can be predicted on the basis of their amino acid homology with HSV genes and genes from other herpesvirus genes such as KSHV. The predictions and known functions are shown in Tables 22.3 and 22.4. These similarities between proteins encoded by the different herpesviruses, such as HSV -1, KSHV, and EBV underscores the relationships between the various herpesviruses. The homologous genes are primarily limited to genes required for the cleavage and packaging of the viral genome and infection of susceptible host cells. Included among the conserved genes are virion structural proteins, enzymes involved in DNA replication, some regulators of gene expression, and glycoprotein genes. Lytic gene function has been primarily described in HSV, because lytic replication is easily observed in tissue culture systems allowing gene function studies. In contrast, EBV and KSHV, which are largely latent in tissue culture systems, have been less amenable to studies of lytic gene function.

Characteristics of the γ-herpesvirus virion

Morphologically, the EBV and KSHV virions are very similar to other herpesvirus virions, consisting of an envelope containing viral glycoproteins (Epstein et al., 1964, 1965). A tegument layer is found between envelope and nucleocapsid. The envelope contains viral transmembrane glycoproteins that mediate attachment and entry, either via fusion or endocytosis. Most glycoproteins of EBV and KSHV are conserved amongst the different herpesvirus families (gB, gH, gL, gM and gN). However, the most abundant envelope glycoproteins of EBV and KSHV are not found in more distant herpesviruses. These are termed gp350/220 and gpK8.1, respectively (Hutt-Fletcher, 1995; Raab et al., 1998). The EBV and KSHV capsids are similar to those of other herpesviruses. The icosahedral capsid shells are composed of 162 capsomers (12 pentons, 150 hexons). It contains the linear, double stranded DNA molecule wrapped around a toroid-like protein core. The three-dimensional structure of the KSHV capsid has been determined by cryo electronmicroscopy using viral particles produced from cultured primary effusion lymphoma (PEL) cells at a resolution of 22 – 24A (Wu et al., 2000).


There has been dramatic progress in the understanding the molecular biology and disease associations of oncogenic γ-herpesviruses like EBV and KSHV. Many years of research on lymphomas induced by EBV and herpesvirus saimiri have identified viral factors that are critical for the proliferative disorders observed with these viruses. Upon infection of naïve B- or T-cells, respectively, differentiation and proliferation are induced in an antigen-independent manner, most likely to expand the pool of virus -infected or -infectable cells. To achieve this goal, both EBV and herpesvirus saimiri make use of transmembrane proteins mimicking constitutively active signaling receptors. In the case of EBV, the latent membrane proteins 1 and 2A are likely essential for the differentiation and expansion of latently infected cells observed in vivo. In herpesvirus saimiri, these latent transmembrane proteins are STP (saimiri transforming protein) and a second protein termed TIP (tyrosine kinase interacting protein) that is found in some strains of herpesvirus saimiri. Usually, this process does not result in the development of malignant disease, but is likely important for the establishment of latency. However, other circumstances can occur which may result in overt malignant disease such as accidental infection of a foreign host, immunosuppression, or infection with malaria. Each of these increases the risk of development of disease associated with viral infection. In addition, genetic changes may occur in infected cells within the host that may also be important for the development of malignant disease. This may be quite rapid as seen in Burkitt’s lymphoma or have a lengthy latency period as seen in Hodgkin’s lymphoma. Besides the latent membrane proteins, other EBV viral proteins such as EBNA 1 (Wilson et al., 1996; Drotar et al., 2003) and the virally encoded small RNAs called the EBERs (Komano et al., 1999; Ruf et al., 2000) may also have a role in EBV -associated malignant diseases in the human host. This will be more fully covered in later chapters.

Several lines of evidence indicate that KSHV plays an essential role in KS pathogenesis: the virus is invariably present in KS, KSHV infection precedes KS -development, the virus is present in the tumor cells themselves, and it is rather infrequently found outside the population at risk of KS (see Chapters 50 and 54). Research on KSHV pathogenesis is hampered by the lack of a cell culture system for transformation and animal models for KSHV proliferative diseases. Studies using rodents transgenic for single KSHV genes have been more successful, but results from such experiments should still be interpreted with caution, no matter how tempting the resemblance of lesions in mice transgenic for vIL8R to KS may be (Yang et al., 2000).

At least two concurring models exist for the role of KSHV in oncogenesis. The “cytokine model” emphasizes the role of inflammatory cytokines induced or produced by KSHV. A closer look at clinical course and histopathology of KS raises doubts about the relevance of “classical,” transforming genes for the pathogenesis of this peculiar tumor. The peculiar pathology of KS hints at a more complex, indirect mechanism of pathogenesis. Based on clinical observations and data derived from cell culture systems, models of KS pathogenesis were developed before KSHV was discovered. Several groups agreed upon the notion that KS develops as an interplay of inflammatory cytokines and angiogenic factors (Ensoli and Stürzl, 1998), although the cytokines focused on varied in different reports. Interestingly, KSHV encodes or induces several cytokines with intriguing similarity to the cellular factors shown to be required for in vitro models of KS. An example is VEGF that is secreted by cells expressing the constitutively active vIL-8R. This leads to a model of KS pathogenesis, where increased secretion of both viral and cellular cytokines, the latter in part induced by KSHV, promote inflammatory infiltrates (vMIP, vIL-6), angiogenesis (vMIP, vIL-8R), and enhance spindle cell proliferation (vIL-6, vIL-8R via VEGF).

The reliable presence of KSHV in the spindle cells may point to additional factors beyond those induced through the 1%–3% productively infected cells, voting for a role more compatible with a typical “oncogenic transformation” model by latently expressed viral genes. Starting from the close relationship to EBV and herpesvirus saimiri, it is intriguing to assume that transmembrane proteins mimicking constitutively active receptors mechanisms, similar to those identified in EBV and herpesvirus saimiri, might be relevant for KSHV pathogenesis. At first sight, KSHV genes K1 and K15 might fall into this category. However, attempts to detect expression of these genes in latently infected tumor cells remain unsuccessful.

Thus, KS may result from a complex interplay of both viral and cellular cytokines and angiogenic factors, induced by a sustained inflammatory reaction initiated by up to 3% productively infected cells. Perhaps the viral cyclin and other latency-associated proteins such as LANA -1 might further enhance the proliferation of KS cells and favor the development of truly malignant cells by indirect means, e.g., the reduced control of accidental DNA damage. As KS is an unusual malignancy, resembling hyperplastic, angioproliferative inflammatory changes rather than true sarcoma, such a multistep/multifactorial model might be more compatible with KS pathogenesis than classical transformation models by viral oncogenes, as described for EBV, herpesvirus saimiri, and possibly for KSHV -associated B-cell malignancies (PEL).


R. L. is a Stohlman Scholar of the Leukemia and Lymphoma Society of America and supported by the Public Health Service grants CA 62234, CA 73507, and CA 93444 from the National Cancer Institute and DE 13127 from the National Institute of Dental and Craniofacial Research. F. N. is supported by the German Research Foundation (SFB466 and SFB 643) and the “Mainzer Akademie der Wissenschaften und der Literatur.” We would like to thank current and former members of the Longnecker, and Neipel laboratories for their contributions to the work described, as well as our many colleagues throughout the world whose work we were unable to formally cite in this chapter.

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