IntroductionHuman T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia-lymphoma (ATLL). 1 Treatment of patients with ATLL using conventional chemotherapy has limited benefit given that HTLV-1 cells are resistant to most apoptosis-inducing agents. 2,3 This may in part be because HTLV-1 leukemic cells overexpress the multidrug resistance protein and the lungresistance protein, resulting in the pumping of a wide spectrum of agents from the plasma membrane and preventing them from entering the cytoplasm. 4,5 In addition, the down-regulation of Fas-ligand expression and rare cases of mutations in the Fas gene sequence have been reported and could also impair the induction of apoptosis through this pathway. 6 In vivo, but not in vitro, the combination of zidovudine (AZT) with interferon-␣ is a partially effective treatment that induces cell death in HTLV-1-infected cells. 7,8 In vitro, retinoic acid 9,10 or arsenic trioxide (As 2 O 3 ), in combination with IFN-␣, can also induce cell death in HTLV-1-transformed cells 11,12 through mechanisms that remain unclear but that may involve the down-regulation of NF-B in the latter case. 13 Programmed cell death, or apoptosis, consists of a highly regulated series of events allowing the organism to control cell number and tissue size. 14 It occurs in 3 phases-initiation, commitment to cell death, and execution. During apoptosis, a complex set of proteins is activated. Among them, caspases play a key role and act as initiators (for review, see 15 ). These cysteine proteases are normally present as pro-enzymes and are proteolytically cleaved to active heterodimers. They have an active-site cysteine and mediate apoptosis by proteolysis of specific substrates. Substrate specificity is determined by the 4-residue amino-terminal to the cleavage site. Caspase-dependent cleavage can either activate or inactivate the target protein. Close to 100 caspase substrates have been reported. 16 Poly (ADP-ribose) polymerase (PARP), a regulator of DNA repair, and Bcl-2 are known substrates of caspase-3. Mitochondria have been recently recognized to play a major role in the control of apoptosis or programmed cell death. 14,17 Members of the Bcl-2 family that interact with the permeability transition pore complex regulate permeabilization of mitochondrial membranes, a decisive feature of early cell death.Bcl-2 is a member of an expanding family of related proteins. Some of them are proapoptotic (Bax, Bak, Bid, Bcl-X S ) and some are antiapoptotic (Bcl-2, Bcl-X L ) (for review, see 14,18 ). It has been shown that the presence of Bcl-2 blocked the activation of caspase-3. However-and adding another level of complexityBcl-2, which inhibits cell death, can also be converted to a Bax-like death effector through its cleavage at Asp-34 by caspase-3. 19,20 Interestingly, Bcl-2 and Bcl-X L are overexpressed in HTLV-1 cells. 21,22 In the latter case, this phenomenon is linked with the constitutive activation of the NF-B pathway by Tax. 23 Tax is a 42-kd protein whose express...

Using mAbs and genomic probe to the CD4 molecule, the HIV receptor, we demonstrated that HIV replication induces the disappearance of its functional receptor from the cell surface by two distinct mechanisms. First, after being expressed onto the cell surface, HIV envelope gp110 will complex CD4, efficiently masking the CD4 epitope used by the virus to bind its receptor. This phenomenon occurs on the surface of each infected cell and is not due to the release of soluble gp110; infection with recombinant HIV/vaccinia viruses expressing a mutated HIV env gene designed to prevent gp110 release from the cell surface induces a similar gp/CD4 complexes formation. Second, virus replication induces a dramatic and rapid loss of CD4 mRNA transcripts, preventing new CD4 molecules from being synthesized. These two mechanisms of receptor modulation could have been developed to avoid reinfection of cells replicating the virus as well as to produce more infectious particles. These results suggest that the classical virus interference documented for other retroviruses might not only be due to receptor/envelope interaction, but might also depend on receptor gene expression.

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