virus-encoded immune evasion genes and genes that inuen-ce cellular prolieration, survival, migration, angiogenesis andcytokine/chemokine production. The host responds to persis-tent viral inection with its own chronic inammatory response,thereby acilitating events that, particularly in the context o immunosuppression, could drive viral oncogenesis. Understan-ding the dynamic relationship between host and viral actorsthat drives KS oncogenesis is central to mounting eective stra-tegies to prevent or ameliorate tumor development. In addition,deciphering KS pathogenesis will enhance our understandingo novel virus-induced mechanisms o tumorigenesis. There isa growing appreciation o the role that chronic inammationplays in cancer development, and KS oers a unique opportu-nity to explore this topic.
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In the late 19th century, Moritz Kaposi rst described KS as a rareand relatively indolent disease o the lower extremities (classicKS). Throughout the 20th century, endemic KS was recognizedin parts o Arica and the Middle East as a common cancer o children and adults. For example, in the pre-AIDS era, endemicKS in central Arica comprised up to 9% o malignant tumors inmales . Today, KS is the most prevalent malignancy amongAIDS patients worldwide, and it has become the most commoncancer in several sub-Saharan Arican countries where KSHV isendemic and HIV is widespread. Compared to the other ormso KS, AIDS-associated KS is an aggressive disease typically ma-niesting with disseminated and even visceral involvement, andhas an untreated median survival o less than 2 years. KS occursin AIDS patients who have not had highly active antiretroviraltherapy (HAART) around 20,000x more oten than in the gene-ral population . In areas where highly active antiretroviraltherapy (HAART) is widely available, there has been a dramaticdecline in KS incidence. However, access to HAART is not uni-versal, and this has led to a KS epidemic in many parts o Ari-ca, along with the resultant potential or disease re-emergenceelsewhere. KSHV-seropositive individuals with other orms o immunodeciency (genetic, iatrogenic, idiopathic) are also atincreased risk (~500x greater than the general population) orKS development . In addition to KS, KSHV is also involved intwo AIDS-associated B-cell cancers, primary eusion lymphoma(PEL), and the plasma cell variant o multicentric Castleman’s di-sease (MCD). KSHV seroprevalence varies geographically anddemographically, and both sexual and non-sexual routes o transmission have been proposed. In the USA, prevalence ran-ges rom approximately 5% among random blood donors to ashigh as 80% among groups o homosexual men . In sub-Sa-haran Arica, where KS was endemic prior to the AIDS epidemic,seroprevalence ranges rom 30-100% .
KSHV is a g-herpesvirus in the Rhadinovirus genus encodingapproximately 87 open reading rames (ORFs), 15 o whichhave no homologues in the other human herpesviruses. Likemost herpesviruses, KSHV has two major modes o replication.In the lytic phase, entry, uncoating, and nuclear import are o-llowed by a coordinated sequence o viral transcription, DNAreplication, and assembly, ollowed by the nal release o nas-cent virions. KSHV can also undergo a “latent” lie cycle whereonly a small subset o viral genes is expressed. Here, ater entryand translocation to the nucleus, the viral DNA circularizes, andmultiple copies are maintained as episomes attached to thehost chromosome via the viral latency associated nuclear anti-gen (Lana-1). Viral genomes are then replicated at roughly thesame rate as the host chromosome, such that each daughter Table 1. KS clinical presentationClassic (sporadic) KSPrimarily aects older non-HIV inected men o Mediterra-nean and Jewish originPatients present with multiocal mucocutaneous lesions,typically as violaceous lesions on the legs, but may inre-quently present solely with KS o the mucosa, genitalia andgastrointestinal tract Visceral and lung involvement portends a poor prognosisArican (endemic) KSCauses lymphadenopathy in young males, but maniests inadults with deeply ulcerating tumors o the lower extremityPresently, it is dicult to dierentiate between true endemicKS and AIDS-associated KSAIDS-related (epidemic) KSMay cause minimal disease or maniest with widespreadlesions resulting in signicant morbidity and mortalitySkin lesions vary rom small papules to large plaques andexophytic or ungating nodulesLymphedema may be extensive and disproportionate to theextent o the cutaneous diseaseExtracutaneous disease is common, and typically involvesthe oral cavity, gastrointestinal tract, lymph nodes, and lungs Transplant (iatrogenic) KSKSHV inection can be associated with atal KS in this setting