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HTLV Tax

Figure 12-13. Tax interferes with Fas/FasL mediated intracellular signaling. Fas surface receptors can mediate apoptosis through two different caspase cascades. The first involves the activation of caspase 8 by molecules that associate with the receptor (similar to the TNF-induced pathway). The second pathway involves the activation of caspase 9 and is dependent on the release of cytochrome C and Apaf-1 from mitochondria (an event mediated by Bax, Bix, and Bad, which act as competitors for members of the Bcl family of anti-apoptotic molecules). Both of these pathways result in the activation of caspase 3 and the cleavage of death substrates that directly mediate apoptotic events. Tax inhibits the first pathway at the level of caspase 8, presumably by trans-activating the FLICE inhibitory protein

(1), although the exact step that is inhibited is unknown. Tax inhibits the second pathway by trans-suppressing Bax

(2) and trans-activating the Bcl-Xl gene via NF-kB activation, increasing the Bcl-Xl:Bax ratio. This prevents the dissociation of Apaf-1, a necessary substituent of the active caspase 9 complex, resulting in protection from apoptosis. Tax can inhibit both pathways by trans-activating XIAP, which can act as a caspase 3 inhibitor, via NF-kB activation (4). (Adapted from Scaffidi et al.,81 with permission.)

matic carriers and ATL patients. These were DRB1*1501 and DRB1*1101. One DQB1 allele had significantly greater frequency. This was DQB1*0602. There was no allele that conferred significantly increased susceptibility to HAM/TSP.

In another report, HLA class I alleles, A36 and B18, were found to be increased among patients with ATL compared with HTLV-1 asymptomatics.106 It is important to note that ATL and HAM/TSP diseases very rarely appear in the same person, and the prevalence of each disease in patients suffering from the other is the same as that of the entire HTLV-1 infected population. Hence, it would seem that the pathogenesis of these two diseases are independent of each other. Since the difference between ATL patients and HAM/TSP patients is in allelic frequencies of certain class II antigens, the basis of that predisposition seems to be immunological.

In vivo experiments with euthymic rats inoculated with HTLV-1-infected cells have shown that suppression of the cellmediated response by co-stimulatory blockade with monoclonal antibodies (mAbs) to both CD80 and CD86 confers susceptibility to developing tumors.107 Other experiments with nude rats showed that tumor development can be suppressed by transferring splenic T cells from immunized rats.108 Immunization in cynomolgus monkeys has shown to provide protective immunity against HTLV-1 infection, presumably by stimulating a strong cell-mediated response to viral antigens.109

The induction of apoptosis of infected cells is important to controlling tumor development, considering that several cases of spontaneous regression of ATL have been directly linked to high peripheral cytotoxic activity.110,111 There have also been studies suggesting the importance of a humoral response to viral envelope glycoproteins to the development of ATL.112 Individuals with ATL express low antibody titers to envelope glycoproteins when compared with asymptomatic carriers and patients who develop HAM/TSP. Taken together, these results strongly suggest that immunocompetent individuals will be able to control an HTLV infection through CTL attack and induction of apoptosis of infected cells and neutralization of circulating virions through an antibody response. This will prevent both the widespread dissemination of the virus and the expansion of malignant clones in the periphery, and decrease the possibility of developing ATL.

HTLV-1-specific, HLA class I-restricted CD8+ CTLs can be found in HAM/TSP patients and asymptomatic HTLV-1 carriers but are barely detectable in ATL patients.112-116 This difference can potentially be explained in the differences in class I and class II allelic frequencies among the different clinical states. Among the class II antigens, asymptomatic carriers and ATL patients have similar allelic frequencies, and have significantly higher frequencies than HAM/TSP patients at these loci. This suggests that the MHC-II mechanism of antigen presentation may have an effect on the proliferative response to HTLV-1 antigens. Perhaps the epitopes presented on DRB1*1501, DRB1*1101, and DQB1*0602 are not very immunogenic, and do not stimulate a strong CD4+ proliferative response. The alleles expressed by HAM/TSP patients, however, are able to express the immunodominant epitopes to HTLV-1, and are therefore able to stimulate a strong proliferative response in HTLV-1-specific CD4+ T cells.

The difference between ATL patients and asymptomatic carriers seems to rely on class I restriction. Perhaps the A36 and B18 class I antigens, expressed at a higher frequency among ATL patients, do not mediate strong specific lysis, and the alleles expressed by asymptomatic carriers do. Therefore, despite the weak proliferative response among the asymptomatic carriers, these individuals are able to lyse infected cells efficiently before they develop a malignant clone. ATL patients do not seem to possess this ability.

The difference in numbers of virus-specific CTLs in asymptomatic carriers and ATL patients, despite a predicted similarity in the proliferative response, could be due to this difference in CTL cytotoxicity between the two clinical states. CTLs that cannot mediate specific lysis of infected cells will be eliminated due to Tax-induced apoptosis. Expression of Tax trans-activates the gene for Fas-ligand (CD95L).117 An infected cell will express high surface levels of Fas-ligand. Infected cells have shown the ability to, in vitro, induce T-cell death by apoptosis.117 Since activated CTLs express Fas, HTLV-1-infected cells will induce apoptosis in antigen-recognizing cells. In ATL patients with CTLs that cannot mediate effective lysis, the virus-specific CTLs would be eliminated at a higher rate than in asymptomatic carriers.

Certain immunological characteristics of the infected individual determine whether HTLV-1 infection will result in the development of ATL. Individuals who can mount a strong immune response, most importantly a strong cell-mediated response, are able to clear infected and transformed cells and are at a decreased risk of developing ATL, although they seem to be at a higher risk for developing autoimmune neurological diseases. In the presence of weak CTL responses, HTLV-1 transformed cells will develop into malignant clones that will go on to cause disease symptoms.

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