Hhv-8 Essay, Research Paper

?Human Herpes Virus-8 (HHV-8) and Kaposi?s Sarcoma (KS)?

Human herpes virus (HHV-8) poses a challenging task for researchers determining its role in Kaposi?s sarcoma (KS). People with KS are distinguished by their placement in four categories. The first category consists of elderly males of Mediterranean or Eastern European Jewish descent. The second category consists of individuals of all ages from Africa. Neither one of these categories is associated with immune deficiency or known environmental factors. The last two categories are associated with organ transplants or HIV-1. In all forms of KS males are predominantly affected.

Kaposi?s Sarcomas are known to harbor cells known as spindle shaped cells (SC). The spindle shaped cells are associated with abnormal blood vessel development and blood leakage. Although, the SC is the most frequently encountered cell in KS tumors it is undetermined if they are neoplastic cells or hyperproliferating cells or an altered cell induced by cytokines (INF-).

Although, it is easy to believe that all cells in a tumor are neoplastic, evidence suggests otherwise. There are three characteristics that are present in all KS cells whether they are neoplastic or not. The first is absence of a histologically distinguishable neoplastic cell. The second is the lack of usual chromosomal abnormalities. The last is a combination of three features angiogenesis, inflammation, and proliferation.

The one factor that brings the four categories of people infected with KS is HHV-8 found in KS tissues. Although, HHV-8 is thought to be connected to KS, HHV-8 itself has very low risk factor for KS development. Most reports on KS indicate a 2% to 10% prevalence of HHV-8 in the world, but in the U.S. there is thought to be a 5% prevalence among men according to a 1970s baseline incidence of KS. In relation to HIV-1 incidence of KS increases by a factor of 20,000 to 50,000 times with the presence of HHV-8.

It is postulated that HIV-1 infections promote HHV-8 replication indirectly by suppression of host immune systems. KS is thought to begin with micro-vascular lesions mediated by different environmental factors for each of the four categories of KS. One of these factors is abnormal cytokine production; in HIV-1 associated KS, this includes an increase in inflammatory cytokines, such as IFN , TNF , and IL-7 that are enhanced by Tat of HIV-1. Tat which is essential for HIV-1 replication is released and taken up by other cells, where it inhibits T-cell proliferation and promotes abnormal cytokine production, adhesion, and growth. Tat interaction with cells is mediated by a RED motif (cell binding motif), which is represented in HIV-1 but not in HIV-2. Thus, KS is less frequently associated with HIV-2.

HHV-8 is thought to be linked to KS by a homologue of a G-protein coupled receptor encoded by ORF 74 (open reading frame 74). This homologue of G-protein is expressed in some KS tissue, which in turn induces angiogenic cytokine such as VEGF (vascular endothelial growth factor). Thus, expression of the homologue leads to cell growth. Although, VEGF is expressed in KS tumors ORF 74 is not expressed in all KS tumors, which suggests a more complex pathway to expressing VEGF than simply expressing ORF 74.

In vitro growth promotion of endothelial cells infected by HHV-8 with results that infected cells are more responsive than uninfected cells to high VEGF. Thus, leaving doubts if whether these effects can be called transformations or immortalization. If HHV-8 is discovered to be a transforming virus inhibition of replication should have no effect on neoplastic cells. Thus, this would be consistent with the reasoning that not all cells of KS tumors are neoplastic.

The detection of HHV-8 DNA sequences in virtually all patients with KS, with or without HIV infection, has allowed researchers to hypothesize a causal role for this virus in the pathogenesis of KS. Studies have shown that homosexual men are more likely to have anti-HHV8 antibodies than individuals at risk with non-sexually transmitted HIV infection and that HHV-8 seroconversion, the presence of antibodies against the HHV-8 latency-associated nuclear antigen, appears before the clinical onset of KS. The virus has also been consistently detected in primary-effusion B-cell lymphomas and in Castleman?s disease.

The extent to which HHV-8 is a universal infectious agent is still unclear. It is not known whether HHV-8 may also be transmitted by routes similar to those of other herpesviruses and whether the mode of transmition may differ according to geographical and socioeconomic settings. Studies of blood donors have shown little or no infection among U.S. blood donors and have shown intermediate and high prevalence rates among Italian and Ugandan blood donors respectively. Studies of children in the U.S. have failed to detect HHV-8 infection, as defined by viral sequences in the peripheral blood mononuclear cells, or have shown low prevalence or the absence of anti-lytic-phase antibodies with no anti-latent-phase antibodies. In contrast HHV-8 DNA sequences have been detected in a high proportion of Japanese children. To test the hypothesis that HHV-8 infection may be acquires way before an individual reaches a sexual activity age, Andreoni and his colleagues evaluated the prevalence of anti-lytic and anti-latent HHV-8 antibodies in Egyptian children.

Antibodies to lytic and latent antigens of HHV-8 were detected by using immunofluorescence assays (IFA?s) based on the BCBL-1 (body cavity B-cell lymphomas) cell lines. The BCBL-1 cells were grown in RPMI-1640 medium with 10% heat-activated fetal calf serum and penicillin antibiotics. The prevalence of antibodies directed against herpesvirus was calculated after stratifying by age. The participants were also stratified by anti-lytic HHV-8 antibody titer. Out of the 246 individuals studied, 44.7% had anti-lytic antibodies against HHV-8. The highest relative increase in the proportion of children with anti-lytic HHV-8 antibodies was observed in the age group 1-3 years, with 20% increase compared with the age group of less than 1 year. The prevalence appeared to stabilize for children who were more than 9 years old. 8.5 % of the total studied had anti-latent antibodies that in turn also had anti-lytic antibodies. Overall, HHV-8 seroprevalence was lower than that of other herpesviruses.

The results of this study suggested that HHV-8 infection is widespread among Egyptian children, showing a non-sexual cause of the disease. The ratio between anti-lytic and anti-latent antibodies was 5.2 : 1 and this may suggest that anti-lytic antibodies are generally present at higher levels than anti-latent antibodies.

With regards to routes of transmition, findings by others suggest that in industrialized countries, HHV-8 infection is likely to be acquired after adolescence, during the sexual active phase. The findings of this study, though, suggests that in developing countries the infection appears to be acquired early in life, as a possible consequence of transmission in the family and in community settings. It has been reported that infectious virus and viral RNAs may be detected in saliva of patients without KS, and it has been suggested that HHV-8, like EBV, undergoes lytic replication in oropharyngeal cells.

With regards to arguments made for direct causative role of HHV-8 in KS, two more powerful arguments have been suggested. One of the arguments points to that the virus is present in peripheral blood mononuclear cells before the appearance of KS and is present in the majority of cells in all but early leasions. Another interpretation suggested by Browning et al. showed that activated endothelial cells could be found in peripheral blood rather infrequently and that these cells were found often in much greater number in patients with KS and also in HIV-1-infected patients before the appearance of KS. The studies of Reitz and his colleagues proposed that this is because of the known increase in the level of IFN-in HIV patients. Such an increase can activate macrophages and endothelial cells and promote their entry into the circulation, presumably to migrate to sites of inflammation. It is possible that some of these cells carry HHV-8 and may home to microscopic KS lesions and other sites of inflammation. It is also possible that, once present, HHV-8 can undergo increased replication because of the inflammatory environment present in these lesions and data suggests that HHV-8 replication is enhanced by inflammatory cytokines.

The reasons why and how HHV-8 causes KS are yet to be found, and from what we have seen from these articles there is confusion or discrepancies in their suggestions. The lack of research with complete conclusive evidence could be due, at least in part, to the absence of a good animal model of spontaneous or induced KS and, in part, to difficulties in culturing KS tumor cell, as suggested by Reitz and his collegues.

REFERENCES

Reitz et al, J Natl Cancer Inst, ?Perspective on Kaposi?s Sarcoma: Facts, Concepts, and Conjectures?, V. 91, Sept 1999, 1453-58

Weiss et al, J Natl Cancer Inst, ? Human Herpesvirus Type 8 and Kaposi?s Sarcoma? V.23, April 1997, 51-54

Andreoni et al, J Natl Cancer Inst, ?High Seroprevalence of Antibodies to Human Herpervirus-8 in Egyptian Children?, V. 91, March 1999, 465

Gallo, Robert, Science, ?The enigmas of Kaposi?s Sarcoma?, V.282, December 1998, 1837-39

Miller, Mike, J Natl Cancer Inst, ? KS Enters Y2K Still Riddled With Many Questions? V. 91, October 1999, 1612-1614