Chapter 26 : Kaposi's Sarcoma-Associated Herpesvirus (KSHV/HHV8)

A phylogenetic tree showing the alpha-, beta- and gammaherpesvirus subfamilies. KSHV belongs to the genus Rhadinovirus, 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 (HVS) in New World monkeys. Herpesviruses from the alphaherpesvirus (e.g., herpes simplex and varicella-zoster virus) and betaherpesvirus subfamilies (e.g., cytomegalovirus and human herpesviruses 6 and 7) have not been found to cause tumors in humans. (From Moore et al. ( 12 ) with permission.)

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, rhesus rhadinovirus, has been found widely distributed among primates including chimpanzees. It is likely that a human version of this virus exists but has not yet been found. (Courtesy of B. Damania, University of North Carolina, Chapel Hill.)

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

The global KSHV seroprevalence, subtype distribution, and migration. KSHV migration might be correlated with the major migrations of modern humans out of Africa over the past 100,000 years.

Electron photomicrographs of KSHV virion formation and egress in a PEL cell line induced into lytic replication with TPA. A. Naked virus capsids are formed in the nucleus of the cell (NM, nuclear membrane). 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). E. The insert shows a high magnification image of the virus with the capsid (C), tegument (T), and envelop (E). (Photos courtesy of Antonella Tosoni, University of Milan.)

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.

Schematic illustration of mechanisms of KSHV latency and reactivation. Expression of KSHV latent products including LANA, vCyclin, vFLIP, and miRNAs enhance/maintain latency by inhibiting KSHV lytic replication, promoting cell survival, and facilitating the viral episome replication and segregation. Several cellular factors such as NF-κB, Hey1, SIRT1, KAP1, and IRF7 as well as cellular miRNAs inducing miR-1258 and miR-320d repress KSHV lytic replication. In contrast, several physiological factors including hypoxia, HIV infection, inflammatory cytokines, oxidative stress, and ROS can induce RTA expression by activating specific cellular pathways and transcriptional factors including MEK/ERK, JNK, p38, AP-1, MSKs, Ets-1, Pin1, HIF1/2, PKC, and Notch. RTA interacts with several host proteins such as XBP-1, Notch, and C/EBPα, as well as viral proteins such as MTA and kb-ZIP to induce the expression of viral lytic genes and activation of the entire viral lytic transcriptional program.

KSHV seroprevalence increases linearly with numbers of recent sex partners in this population-based sampling of gay and bisexual men (sera collected in 1984) from San Francisco. This and related risk-factor data suggests that KSHV is sexually transmitted although the precise mechanism for transmission remains unclear. (From Martin et al., ( 319 ) with permission.)

Map of KS prevalence throughout Africa prior to the AIDS epidemic. This map was constructed from surveys performed by Denis Burkitt who first described Burkitt's lymphoma. It is evident that KS was hyperendemic throughout this continent. With the onset of the AIDS epidemic, a second epidemic of KSHV-related cancer has occurred and KS is the most commonly reported cancer in most sub-Saharan African countries.

A. Typical appearance of KS lesions on arm and chest for an AIDS patient. B. KS frequently involves mucosal surfaces, in this case sublingual palette. C. Disseminated skin KS occurring in a dermatomal distribution on the back of an AIDS patient. D. An AIDS patient's leg showing post-radiation hyperpigmentation, ulceration, and nodular KS lesions that have recurred within the radiated area. (Photos courtesy of Bruce Dezube, Beth Israel Deaconess, Boston, MA, and Susan E. Krown, Memorial Sloan-Kettering Cancer Center, NY, NY.)

A. A photomicrograph of KS tumor infiltrating the duodenum on an AIDS patient. All forms of KS (both HIV+ and HIV−) have similar histologic appearances. Vascular clefts (arrows) within the tumor are filled with red cells, giving the tumor its characteristic reddish-brown appearance. A mononuclear infiltrate in the tumor can be present but cellular atypia or pleomorphism is generally uncommon in KS lesions (×40 magnification). B. Typical speckled nuclear staining pattern (brown) for LANA1 antigen can be seen in many cells of a skin KS tumor (×60 magnification). (Photos courtesy of Liron Pantanowitz, University of Pittsburgh, Pittsburgh, PA.)

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 0. 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 1:50,000 dilution or greater. (From Gao et al., ( 9 ) with permission.)