Sandbox: Kaposi

Pathophysiology

• Kaposi's sarcoma arises from endothelial cells, which are epithelial cells that are normally lines the interior surface of blood vessels and lymphatic vessels.

Kaposi's sarcoma (KS) is a tumor caused by Human herpesvirus 8 (HHV8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV).

Despite its name, it is generally not considered a true sarcoma, which is a tumor arising from mesenchymal tissue.

KS actually arises as a cancer of lymphatic endothelium and forms vascular channels that fill with blood cells, giving the tumor its characteristic bruise-like appearance.

Micrograph of a Kaposi's sarcoma showing the characteristic spindle cells, high vascularity and intracellular hyaline globs. H&E stain.

KS lesions contain tumor cells with a characteristic abnormal elongated shape, called spindle cells.

The tumor is highly vascular, containing abnormally dense and irregular blood vessels, which leak red blood cells into the surrounding tissue and give the tumor its dark color.

Inflammation around the tumor may produce swelling and pain.

Although KS may be suspected from the appearance of lesions and the patient's risk factors, definite diagnosis can be made only by biopsy and microscopic examination, which will show the presence of spindle cells.

Detection of the KSHV protein LANA in tumor cells confirms the diagnosis.

Virology

KSHV is a herpesvirus, and is a large double-stranded DNA virus with a protein covering that packages its nucleic acids, called the capsid, which is then surrounded by an amorphous protein layer called the tegument, and finally enclosed in a lipid envelope derived in part from the cell membrane. KSHV has a genome which is approximately 165,000 nucleic acid bases in length. It is a rhadinovirus, and is remarkable since it has stolen numerous genes from host cells including genes that encode for complement-binding protein, IL-6, BCL-2, cyclin-D, a G protein-coupled receptor, interferon regulatory factor and Flice inhibitory protein (FLIP), as well as DNA synthesis proteins including dihydrofolate reductase, thymidine kinase, thymidylate synthetase, DNA polymerase and many others. While no other human tumor virus possesses these same genes, other tumor viruses target the same cellular pathways illustrating that at a basic level, all tumor viruses appear to attack the same cellular control pathways, so-called tumor suppressor pathways.[citation needed]

After infection, the virus enters into lymphocytes via macropinosomes where it remains in a latent ("quiet") state expressing the viral latency-associated nuclear antigen, LANA. The virus exists as a naked circular piece of DNA called an episome and uses the cellular replication machinery to replicate itself. LANA tethers the viral DNA to cellular chromosomes, inhibits p53 and retinoblastoma protein and suppresses viral genes needed for full virus production and assembly ("lytic replication"). Various signals such as inflammation may provoke the virus to enter into lytic replication. When this occurs, the viral episome starts replicating itself in the form of linear DNA molecules that are packaged into virus particles which are expelled from the cell, to infect new cells or to be transmitted to a new host. When the virus enters into lytic replication, thousands of virus particles can be made from a single cell, which usually results in death of the infected cell.

The viral genome consists of a ~145 kbase long unique region, encoding all of expressed viral genes, which is flanked by ~20-30 kbases of terminal repeat sequences.[9] Each terminal repeat unit is 801 bp in length, has 85% G+C content and is oriented in a repetitive head-to-tail fashion. During latency, the virus genome depends on the host replication machinery and replicates as closed circular episome ("plasmid") using sequences within the terminal repeats as a replication origin. When the virus reactivates into lytic replication, it is believed that the virus genome is replicated as a continuous linear molecule off from an episome (so called rolling circle model). As each unit genome is replicated, it is cut within the terminal repeat region, and then packaged into a virus particle (virion). The virus then becomes enveloped with a lipid membrane as it transits the nucleus and the cytoplasm to exit the cell. Thus, whereas KSHV genome is circular in the nucleus of latently infected cells, it is packaged into infectious viruses as a linear molecule. Once the virus newly infects a cell, the lipid membrane is shed and the virion travels to the nucleus. The viral genome is released where it recircularizes through a poorly understood process that appears to involve homologous recombination.

The primary viral protein responsible for the switch between latent and lytic replication is the ORF50 Replication Transactivation Activator (RTA). When cell signaling conditions activate the generation of RTA, it in turn activates synthesis of a stereotypic cascade of secondary and tertiary viral proteins that ultimately make components of the virus capsid and also the DNA synthesis enzymes required to replicate the virus genome

Transmission

In Europe and North America, KSHV is transmitted through saliva. Thus, kissing is a theoretical risk factor for transmission. Higher rates of transmission among gay and bisexual men have been attributed to "deep kissing" sexual partners with KSHV. Another alternative theory suggests that use of saliva as a sexual lubricant might be a major mode for transmission. Prudent advice is to use commercial lubricants when needed and avoid deep kissing with partners with KSHV infection or whose status is unknown.

KSHV is transmissible during organ transplantation and to a lesser extent through blood transfusion. Testing for the virus before these procedures is likely to effectively limit iatrogenic transmission.

They used representational difference analysis (a method to subtract out all of the human DNA from a sample) to isolate the viral genes.
They then used these small DNA fragments as starting points to sequence the rest of the viral genome in 1996. 
This, the eighth human herpes virus (HHV-8)—now known as Kaposi's sarcoma-associated herpesvirus (KSHV)—has since been found in all KS lesions tested, and is considered the cause of the disease. 

KSHV is a unique human tumor virus that has incorporated cellular genes that cause tumors into its genome ("molecular piracy");

the stolen cellular genes may help the virus escape from the immune system, but in doing so it also causes cells to proliferate. 
It is related to Epstein-Barr virus, a very common herpes virus that can also cause human cancers.