Chapter 25 : Kaposi’s Sarcoma-Associated Herpesvirus

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Kaposi’s sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8 (HHV-8), is a large double-stranded DNA herpesvirus that causes Kaposi’s sarcoma (KS) as well as some malignant and hyperplastic lymphoid disorders. KSHV also resides as a latent virus in infected cells. In contrast to lytic replication, latent viral gene expression provides proliferation and survival factors that inhibit premature cell death. Initiation of lytic replication begins with a highly choreographed cascade of gene expression that determines the sequence of events leading to linear genome replication, virion synthesis, genome packaging, and egress of the virus from the infected cell. Although the incidence of AIDS-associated KS declined 70 to 90% after the introduction of effective antiretroviral therapy, these drugs do not inhibit KSHV infection, and a second emergence of KS among persons with low HIV loads and high CD4 cell counts has been reported. Although KSHV is poorly transmissible through transfusion, transfusion transmission can occur and may cause silent transmission and disease. Studies of AIDS patient cohorts show that KS can develop within weeks or months of primary infection, and in one case, an HIV-positive man developed transient angiolymphoid hyperplasia with microscopic foci of KS spindle cells immediately after infection. The majority of Castleman’s disease is of the hyaline-vascular variant, which presents as solitary lymph node hyperplasia typically in the mediastinum or retroperitoneum. Among AIDS patients, the most effective control measure for KS is effective antiretroviral therapy. The rate of new KS diagnoses is markedly lower among persons on highly effective antiretroviral therapy.

Citation: Moore P, Chang Y. 2009. Kaposi’s Sarcoma-Associated Herpesvirus, p 537-558. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch25
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Image of FIGURE 1

Electron photomicrographs of KSHV virion formation and egress in a PEL cell line induced into lytic replication with tetradecanoyl phorbol acetate. (A) Naked virus capsids formed in the nucleus of the cell (nuclear membrane [NM]); (B) virions budding through the nuclear membrane and becoming enveloped viruses; (C) transit of the virus through the cytoplasm (arrow); (D) egress of the fully enveloped virus from the cell plasma membrane (PM). The inset (E) shows a high-magnification image of the virus with the capsid, tegument, and envelope. (Photos courtesy of Antonella Tosoni, University of Milan.)

Citation: Moore P, Chang Y. 2009. Kaposi’s Sarcoma-Associated Herpesvirus, p 537-558. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch25
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Image of FIGURE 2

Phylogenetic tree showing the alpha-, beta-, and gammaherpevirus subfamilies. KSHV belongs to the genus also known as γ-2 herpesviruses, in the lymphotrophic gammaherpesvirus subfamily. Other related gammaherpesviruses are also associated with lymphoproliferative disorders, including EBV in humans and herpesvirus saimiri in New World monkeys. Herpesviruses from the alphaherpesvirus (e.g., herpes simplex virus [HSV] and varicella-zoster virus [VZV]) and betaherpesvirus (e.g., CMV and HHV-6 and -7) subfamilies have not been found to cause tumors in humans. (Reprinted from reference with permission.)

Citation: Moore P, Chang Y. 2009. Kaposi’s Sarcoma-Associated Herpesvirus, p 537-558. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch25
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Image of FIGURE 3

Old World primate hosts and their gammaherpesviruses. It is evident from this phylogenetic tree that these are ancient viruses that have coevolved with their hosts. A second rhadinovirus, RRV, has been found to be widely distributed among primates, including chimpanzees. It is likely that a human version of this virus exists but has not yet been found. (Reprinted from reference with permission of Cambridge University Press.)

Citation: Moore P, Chang Y. 2009. Kaposi’s Sarcoma-Associated Herpesvirus, p 537-558. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch25
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Image of FIGURE 4

Schematic diagram of KSHV enveloped virus structure. The capsid is composed of hexons, pentons, and triplexes arranged in an icosahedral lattice that contains the virus genome. This is surrounded by an amorphous tegument layer composed of viral and cellular proteins and viral RNAs that are microinjected into the cell on infection. The bilayer envelope surrounding the tegument contains viral glycoproteins, such as gB, that act as receptor and entry proteins.

Citation: Moore P, Chang Y. 2009. Kaposi’s Sarcoma-Associated Herpesvirus, p 537-558. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch25
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Image of FIGURE 5

Genomic map of KSHV sequenced from the BC-1 KSHV-infected PEL cell line. The viral genome contains an ~145-kb LUR flanked on both sides by reiterated terminal repeat (TR) units of high GC content (>85%). Conserved herpesvirus gene blocks are interspersed with blocks containing genes unique to KSHV and other rhadinoviruses. These nonconserved regions contain numerous homologs to host cell genes involved in cell cycle regulation, apoptosis, and immune regulation.

Citation: Moore P, Chang Y. 2009. Kaposi’s Sarcoma-Associated Herpesvirus, p 537-558. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch25
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Image of FIGURE 6

KSHV seroprevalence increases linearly with numbers of recent sex partners in this population-based sampling of homosexual and bisexual men (sera collected in 1984) from San Francisco, CA. This and related risk factor data suggest that KSHV is sexually transmitted, although the precise mechanism for transmission remains unclear. (Reprinted from reference with permission of the Massachusetts Medical Society.)

Citation: Moore P, Chang Y. 2009. Kaposi’s Sarcoma-Associated Herpesvirus, p 537-558. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch25
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Image of FIGURE 7

(A) KS on the face and neck of a patient with AIDS. These cutaneous lesions have a characteristic purple-red appearance. The neck lesions demonstrate the often-noted dermatomal distribution as well as the elliptical outline of cutaneous KS. (Courtesy of David Silvers, Columbia University College of Physicians and Surgeons, New York, NY.) (B) KS frequently involves mucosal surfaces. (C) A leg showing postradiation hyperpigmentation, ulceration, and nodular KS lesions that have recurred within the radiated area. (Panels B and C courtesy of Susan E. Krown, Memorial Sloan-Kettering Cancer Center, New York, NY.)

Citation: Moore P, Chang Y. 2009. Kaposi’s Sarcoma-Associated Herpesvirus, p 537-558. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch25
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Image of FIGURE 8

A photomicrograph of a KS tumor, immunostained for LANA1, infiltrating the dermis from a patient with AIDS-KS. All forms of KS (both HIV positive and HIV negative) have a similar histologic appearance. Vascular clefts (arrows) within the tumor are filled with red cells, most of which have been lost during tissue preparation. A mononuclear infiltrate in the tumor can be present, and cellular atypia or pleomorphism is generally uncommon in KS lesions. The characteristic speckled nuclear staining pattern (open arrows) for LANA1 can be seen in many of the cells.

Citation: Moore P, Chang Y. 2009. Kaposi’s Sarcoma-Associated Herpesvirus, p 537-558. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch25
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Image of FIGURE 9

Antibody responses to KSHV infection are persistent for years after initial infection. This graph shows the reciprocal end-point titers for six men with AIDS who seroconverted to LANA1 IFA positivity at time zero. Antibody positivity remained stable for up to 8 years, until the patients developed KS (marked with an X). Note that anti-LANA1 titers are plotted on a log scale and in some patients can be positive at a dilution of 1:50,000 or greater. (Reprinted from reference with permission of Macmillan Publishers Ltd.)

Citation: Moore P, Chang Y. 2009. Kaposi’s Sarcoma-Associated Herpesvirus, p 537-558. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch25
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Selected KSHV proteins and their known or putative functions

Citation: Moore P, Chang Y. 2009. Kaposi’s Sarcoma-Associated Herpesvirus, p 537-558. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch25
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Patterns of KSHV infection and KS prior to the AIDS epidemic

Citation: Moore P, Chang Y. 2009. Kaposi’s Sarcoma-Associated Herpesvirus, p 537-558. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch25
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Serologic antigen assays for detecting KSHV infection

Citation: Moore P, Chang Y. 2009. Kaposi’s Sarcoma-Associated Herpesvirus, p 537-558. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch25

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