© 1998 by Oxford University Press
Journal of the National Cancer Institute Monographs, No. 23, 55-57,
1998
© 1998 Oxford University Press
Some Aspects of the Pathogenesis of HIV-1-Associated Kaposi's Sarcoma
*Correspondence to: Robert C. Gallo, M.D., Institute of Human Virology, University of Maryland at Baltimore, 725 W. Lombard St., 3rd Floor, Baltimore, MD 21201-1192.
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Abstract |
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 Top Abstract IntroductionHHV-8 (KSHV) and KSReferences |
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Kaposi's sarcoma (KS) is a very rare tumor except after human immunodeficiency virus type 1 (HIV-1) infection when it becomes common. Most investigators assume that the role of HIV-1 is passive, i.e., via inducing immune deficiency, thereby enhancing cancer development, and specifically, in the case of human herpesvirus 8 (KSHV) by enhancing HHV-8 replication. We suggest that the role of HIV-1 is more active in the disease process by at least two events: 1) promoting an increase in inflammatory cytokines, which through sustained release influences early stage KS by inciting local microinflammatory responses, and 2) by the Tat protein that effects growth of the inflammatory cells. Cultures of all activated endothelial spindle cells, whether hyperplastic or neoplastic, are negative for HHV-8; transmission of HHV-8 does not induce cell growth or transformation; monkeys immune suppressed by simian immunodeficiency virus infection and infected also with HHV-8 do not develop KS; polymerase chain reaction analysis of blood cells shows HHV-8 sequences in monocytes and B cells (about 20% of normal donors in Maryland); M. Starzl showed that early KS has few cells (mostly macrophage) positive for HHV-8, increasing and present in endothelial cells only late in the disease; no increase in HHV-8 has been found in association with progressive immune deficiency; and recent studies in Gambia by others showed that HHV-8 is a very common infection, and though HHV-2 is known to be relatively common, HIV-1 is unusual and so is KS. Collectively, these findings lead me to conclude that there is little evidence that HHV-8 is a transforming virus as has been repeatedly suggested and that its role in KS is more likely to be indirect (like HIV-1), perhaps necessary but hardly likely to be sufficient for KS development.
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Introduction |
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TopAbstractIntroductionHHV-8 (KSHV) and KSReferences |
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Beginning in 1987, my colleagues and I have studied Kaposi's sarcoma (KS) cells in culture and after xenotransplantation to nude mice in an effort to gain insight into the nature of KS tumor cells and possibly to shed light on its pathogenesis (1,2). Our findings are consistent with the idea that the KS spindle cells (SCs) are chiefly activated vascular endothelial cells (ECs). The vast majority of successfully cultured cells were normal diploid, grew only transiently in nude mice, and induced angiogenesis in these animals by release of cytokines (1,2). We noted that inflammatory cytokines—interleukin 1 (IL-1), IL-6, oncostatin M, and interferon gamma (IFN
), known to be
elevated in HIV-1-infected persons (3)—promoted growth of these cells (1,4). Interestingly, IFN can convert ECs from
cuboidal to spindle shape and promotes the migration of these
cells into the circulation, presumably in search of an
inflammatory lesion. IFN also activates the expression of
integrins on EC as well as several cytokines (5). The "culturable" KS SCs themselves
produce high levels of cytokines, such as platelet-derived growth
factor (PDGF), IL-6, IL-1, and, notably, basic fibroblast growth
factor (bFGF) and vascular endothelial cell growth factor
(VEGF), both of which are potent angiogenic molecules (6,7). We have provided data that bFGF is
important to sustain growth of the hyperplastic cells (2,4), and Masood and colleagues (8) provided evidence that VEGF is
important for neoplastic cells. The inflammatory cytokines also
promote increased expression of adhesion molecules that
facilitate greater interactions of leukocytes and ECs. This
includes HIV-1-infected CD4 T cells and macrophages. We showed
that the Tat protein of HIV-1 is actively released into the
extracellular fluid (9), and others showed
that it is taken up by nearby cells (9-11). We showed it is also taken up by KS SCs (12). Our results indicate that Tat, at levels released
by cells, promotes the migration, invasiveness, and growth of KS
SC and that these effects are mediated by the RGD motif of Tat
and by its basic region (11,12); the RGD
region, through its molecular mimicry of fibronectin and
vitronectin, interacts with integrins, whereas the basic region,
by competing with bFGF for binding to heparin sulfate
proteoglycans, allows more free soluble bFGF available for growth
promotion (13). ECs require two signals
for growth: adhesion and growth promotion. Both are augmented by
HIV-1 infection. Whether KS is hyperplastic or neoplastic remains debatable. There are results and arguments for both. Reports indicate that many KS patients have tumors which are clonal (14), and we and others have succeeded in isolating neoplastic clones from a few patients (KS Y-1 and KS SLK, respectively) (15,16). Of possible importance is the result showing similar chromosomal markers in both neoplastic cell lines (17). At this time, we can conclude that a significant component of cells of a KS lesion (and perhaps all cells in some patients) are hyperplastic, whereas neoplastic cells can be found in some. One interpretation is that all KS lesions have neoplastic cells from the start, but akin to the Reed-Sternberg cells of Hodgkin's disease they recruit normal cells and remain in the minority but in KS are not morphologically distinguishable as are the Reed-Sternberg cells. Alternatively, KS may begin as a hyperplasia, and only in some patients does a neoplastic transformation occur. We may be able to obtain a definitive answer to this problem if we are able to generate a specific probe based on the karyotypic common abnormality found in the short arm of chromosome 3 in the two neoplastic cell lines (17).
KS is rare and usually not aggressive except in association with HIV-1 infection. Most investigators suggest that the role of HIV-1 is passive, i.e., in inducing immune suppression. In some unexplained way, this is supposed to increase the incidence of cancer. However, with the exception of lymphomas, this has not been demonstrated. Others, such as R. Weiss (these meetings and report from the October 1995 Pasteur Vaccine meeting), suggested that HIV-1-induced immune suppression may favor HHV-8 replication. However, there is no evidence for increased HHV-8 with increasing immune suppression. Furthermore, it is clear that immune suppression occurs without KS development, e.g., congenital, chemotherapy-induced, radiation-therapy induced, or, more to the point, after HIV-2 infection or SIV in monkeys, both of which may produce immune suppression but neither promoting KS. It is of interest, in this regard, that the Tat of SIV and HIV-2 lacks the RGD domain. Finally, KS can occur in the absence of any known immune suppression; e.g., it can be the first sign of HIV-1 infection. Additionally, in non-HIV-1, KS-associated immune suppression is generally not found, e.g., African endemic KS. It is also unlikely that it is a significant feature of classical KS. As noted above, we suggest that the role of HIV-1 in KS is active in its promotion of inflammatory cytokines and by its Tat protein (3), thereby creating microvascular inflammatory lesions that I suggest are the pre-KS lesions.
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HHV-8 (KSHV) and KS |
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TopAbstractIntroductionHHV-8 (KSHV) and KSReferences |
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This virus must be involved in the cause of KS if it is not ubiquitous (which seems to be the case), because it is almost always found in KS lesions. Before a final acceptance of this, however, more refined epidemiologic data with HHV-8 are needed. Originally, it was said by Cesarman et al. (18) to be very rare and virtually limited to KS, but soon after, a higher prevalence was found (19), which seems to be steadily edging upward. A true understanding of its prevalence is probably not yet known. I believe a coordinated study by polymerase chain reaction analysis of separated blood cell populations in multiple laboratories of multiple populations will be the best answer to this problem. Currently, we can estimate it as at least 5% of most populations and likely substantially higher. Recent serology of Gambians by R. Weiss (reported at the International Meeting on Herpes 6, 7 and 8 in Pisa, Italy, June 1997) showing HHV-8 infection in at least 64% of people is disturbing because KS is unusual in Gambia. Of interest and compatible with our hypothesis is that, although HIV-2 is common in Gambia, HIV-1 is unusual.
Chang and Moore (these meetings and elsewhere) have argued that HHV-8 is a transforming virus. Mostly, this has been based on indirect suggestions: 1) its presence in KS lesions; 2) its relatedness to Epstein-Barr virus (EBV) and herpes saimiri; and 3) its genome containing homologues of cellular genes, some of which are involved in cell growth. However, EBV very rarely causes cancer and as Fleckenstein noted (these meetings), neither herpes saimiri or any Rhadinovirus (like HHV-8) have ever been shown to cause disease in their own host. Finally, having some genome homology does not make HHV-8 equivalent to these viruses. Needless to emphasize, some homology to cellular genes says nothing about the capacity to transform. It only offers leads to a virus known to be transforming.
We have been impressed by the fact that, when directly studied, HHV-8 has not only not transformed cells, it has not promoted growth of any primary cells and most importantly not of EC. Moore (this meeting) described DNA of HHV-8 transforming NIH 3T3 cells. However, the limitations of this assay are well known, and the data are not yet available for scrutiny. Moreover, this artificial assay cannot be used to say a virus is transforming. The NIH 3T3 cells are already immortal, and many kinds of DNA lead to these cells promoting tumors in nude mice. Indeed, DNA from HIV-6 can also do the same as well as DNA of some adenoviruses, neither of which is implicated in human cancer.
As already noted, our cultured hyperplastic cells (KS #1-14) and all known cultured neoplastic KS cell lines (KS Y-1 and KS SLK) are HHV-8 negative (20). Furthermore, monkeys infected with SIV (immune deficient as a result) and also infected with HHV-8 do not develop KS (unpublished results of Colombini in our group in collaboration with Biberfeld). These findings and the recent Gambia data (low KS, high prevalence of HHV-8) would lead me to the hypothesis that HHV-8 is not likely to cause KS as a transforming virus. If ultimately found to be ubiquitous, it could still be only a passenger virus. However, this seems unlikely. I favor the idea that it plays an enhancing and likely an essential role in the origin of KS, albeit like HIV-1 likely to be an indirect one, i.e., not simply by infecting a cell and transforming this cell into a neoplastic cell. Instead, I suggest that HHV-8 is recruited to microinflammatory lesions and promotes growth of such lesions (by augmentation of cytokine release?). Our preliminary results indicate that the same inflammatory cytokines which increased after HIV-1 infection and which themselves promote microinflammatory changes also promote HHV-8 replication (unpublished observations of S. Colombini). The converse may also be true and needs testing; i.e., does HHV-8 stimulate the production of growth-promoting cytokines bFGF, VEGF, IL-6, etc., and/or promote growth by contributing, through its own gene products, homologs of cellular inflammatory cytokines?
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References |
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TopAbstractIntroductionHHV-8 (KSHV) and KSReferences |
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1
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