HHV-8 is a member of the gammaherpesvirus subfamily, showing greatest nucleotide homology to members of the genus Rhadinovirus. The existence of this virus was initially recognized by using representational difference analysis of nucleic acids from tissues of a KS patient. The deoxyribonucleic acid (DNA) fragments obtained by this procedure had regions of homology to late genes of other gammaherpesviruses.¹ Since the initial discovery, HHV-8 has been found in all forms of KS: classic, endemic, and acquired immunodeficiency syndrome (AIDS) associated. Because of its association with KS, it is also known as Kaposi’s sarcoma associated herpesvirus (KSHV). Similar to other herpesviruses, strain variations in HHV-8 have also been found. The strain variations are mainly due to variations in the gene products of KSHV open reading frame (ORF)-K1 and ORF-K15. Both of these seem to code for membrane-signaling proteins and may play a key role in the biology and disease manifestation associated with HHV-8.⁴ Three distinct strains of HHV-8 have been identified, which appear to be restricted in their geographic distribution: B and C are the most common in Africa, whereas A predominates in the Mediterranean region. Geographic strain variations in gene sequences have also been identified in virus isolated from Japan, Kuwait, Europe, Russia, Australia, South America, United States of America, and Saudi Arabia.^5,6,7,8,9

HHV-8 does not readily infect most cell types. Thus far, no primary cell or cell line is permissive to HHV-8 infection and none can produce infectious virus. However, several investigators have shown the transmission of HHV-8 DNA from BC-1 cell line into Raji (EBV positive B-cell line), BJAB (EBV negative B-cell line), Molt-3, and owl monkey kidney (OMK) cell lines and cord blood mononuclear cells.^10,11 HHV-8 from KS lesions has also been propagated in embryonic kidney 293 cells. In all these cells, active infection was not noticed and the viral DNA was not detected after a few passages.¹² About 38 additional cell lines, including B cells, endothelial cells, and cells of fibroblastic origin were used as targets for transmission, but all failed.

Primary cultures of human monocytes/macrophages from patients with AIDS-associated KS can be infected with HHV-8, and treatment with cytokines seems to enhance viral production and allow the cells to maintain the virus for a longer period.¹³ Microvascular endothelial cells transformed with papilloma virus type 16 genes, E6 and E7, were also permissive to HHV-8 from BC-1 cell line.¹⁴ Untransformed primary fetal microvascular endothelial cells have also been successfully infected with HHV-8 from a primary effusion lymphoma (PEL) cell line.^15,16

HHV-8 exhibits typical herpesvirus morphology of 100 to 150 nm-enveloped particles. The capsids are icosahedral with a diameter of 90 to 110 nm, which consists of 162 hexagonal capsomeres. The tegument is a protein-containing region between capsid and the envelope. Electron micrographs clearly indicated that the core is a complex of DNA and protein. About 35% of the virion is usually intact, and 65% is defective.¹⁷ The double-stranded linear DNA genome of the virus has been estimated to be 165 to 170 kilobase (kb).¹¹ The genome of HHV-8 is similar to herpesvirus saimiri (HVS) found in squirrel monkeys. It has a single contiguous region, 140 to 145 kb, containing all the coding regions. The genome has repeats of 803 bp in length that are 85% guanine and cytosine. Each DNA molecule harbors about 35 to 45 repeat units.^18,19

When the envelope glycoproteins of HHV-8 bind proteoglycans on the surface of the host cells, penetration occurs by fusion of viral envelope with plasma membrane of the cell. Following insertion into the host genome, DNA replication and capsid assembly occur in the nucleus of the host cell.^11,12

Infectious virus has been isolated from body cavity-based B-cell lymphoma cells.²⁰ In some cell lines derived from these lymphomas, EBV is also present, and both viruses may be latent.²¹ HHV-8 in these cell lines can be reactivated to produce viral particles.^20,22 Virus transcripts have also been detected in endothelial-derived spindle cells from tumors of KS.²³ HHV-8 is transmissible to B cells and replicates in the peripheral blood mononuclear cells of KS patients.^10,24

HHV-8 expresses unique polyadenylated (poly A) nuclear ribonucleic acid (RNA) that colocalizes with uracil (U) small nuclear RNA but not with polysomes, suggesting a regulatory role for the RNA.²⁵ In the latently infected B-cell lymphoma cell lines and KS cells, the genome exists in a circular form, similar to that described for other herpesviruses during latency.²⁶ In KS, transcription of viral genes is restricted; only two transcripts are detected: one for a possible membrane protein and the second the abundant, poly A-containing nuclear transcript.²⁷

The exact nature of the steps involved in the DNA replication is unknown. The whole viral genome has been sequenced. Of the approximately 95 genes comprising the HHV-8 genome, nearly 25 encode novel proteins not found in other HHVs. HHV-8 contains regions encoding homologues of several cellular genes that have regulatory roles in the immune response.^18,28 KSHV carries 11 ORFs that encode homologues to cellular proteins involved in signal transduction, cell cycle regulation, transformation, and/or inhibition of apoptosis.^29,30,31,32