IntroductionThe human T-cell leukemia virus type 1 (HTLV-1), a deltaretrovirus, is the etiologic agent of a severe and fatal lymphoproliferative disorder of CD4 ϩ T cells, the adult T-cell leukemia (ATL), and the neurodegenerative, inflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). [1][2][3][4] These diseases develop as a consequence of prolonged viral persistence in T cells.As emerged from many observations, HTLV-1 has developed a unique strategy for lifelong persistence in the presence of an active immune system. It is characterized by (a) replication of the virus mainly in its provirus form, (b) stimulation of cell division by the virus, and, as a consequence, (c) clonal amplification of infected cells. Evidence that HTLV-1 rarely replicates via reverse transcription but mostly by division of infected cells using cellular DNA polymerase is provided by the high HTLV-1 reverse transcriptase error rate, which is comparable to other retroviruses, 5 and the low mutation rate of the HTLV-1 genome. 6 The stimulation of T-cell proliferation in patients by viral gene expression was substantiated recently by cell dynamic studies. 7 They revealed the correlation of the in vivo proliferation rate of CD4 ϩ CD45RO ϩ cells with viral expression (ex vivo). Another indication that HTLV-1 stimulates growth and survival of T lymphocytes is provided by their expansion to detectable clones, which can persist over many years even in nonleukemic individuals. 8,9 Finally, the virus' ability to stimulate permanent T-lymphocyte growth in vitro, resulting in T-cell immortalization, 10 completes the arguments in favor of viral gene functions as cause of host cell proliferation and clonal expansion of patients' lymphocytes.Besides structural proteins, HTLV-1 encodes the regulatory proteins Tax and Rex, which are essential for viral replication, 11 and the accessory proteins p12, p30, p13, 12,13 and HBZ. 14 While Tax strongly enhances viral mRNA synthesis by transactivating the HTLV-1 long terminal repeat promoter, Rex controls the synthesis of the structural proteins on a posttranscriptional level. 15,16 Although the accessory proteins are important for viral infectivity and replication, 12,17 p12, p13, p30, and HBZ are not required for lymphocyte immortalization. [18][19][20] Tax is able to stimulate transcription by interacting with various signaling pathways. It activates nuclear factor kappa B (NF-B) by 2 pathways. While the canonical pathway is induced by binding and stimulating IKK␥, a component of the inhibitor of kappa B kinase, 10,17 the activation of the noncanonical pathway is less well understood. Transactivation of various cellular promoters is mediated by Tax via direct contact with transcriptional activators CREB and SRF and with the coactivators p300/CBP. 11,21 Tax confers the transforming properties on HTLV-1. 10 The protein can immortalize T lymphocytes 22,23 and induce leukemia in transgenic mice. 24 Biochemically, several Tax functions may contribute to its transforming capacity....
In human T-lymphotropic virus type 1 (HTLV-1) infection, a high frequency of HTLV-1-specific CTLs can co-exist stably with a high proviral load and the proviral load is strongly correlated with the risk of HTLV-1-associated inflammatory diseases. These observations led to the hypothesis that HTLV-1 specific CTLs are ineffective in controlling HTLV-1 replication but contribute to the pathogenesis of the inflammatory diseases. But evidence from host and viral immunogenetics and gene expression microarrays suggests that a strong CTL response is associated with a low proviral load and a low risk of HAM/TSP. Here, we quantified the frequency, lytic activity and functional avidity of HTLV-1-specific CD8+ cells in fresh, unstimulated PBMCs from individuals with natural HTLV-1 infection. The lytic efficiency of the CD8+ T cell response—the fraction of autologous HTLV-1-expressing cells eliminated per CD8+ cell per day—was inversely correlated with both the proviral load and the rate of spontaneous proviral expression. The functional avidity of HTLV-1-specific CD8+ cells was strongly correlated with their lytic efficiency. We conclude that efficient control of HTLV-1 in vivo depends on the CTL lytic efficiency, which depends in turn on CTL avidity of Ag recognition. CTL quality determines the position of virus-host equilibrium in persistent HTLV-1 infection.
Natural killer (NK) cells and dendritic cells (DC) are thought to play critical roles in the first phases of HIV infection. In this study, we examined changes in the NK cell repertoire and functions occurring in response to early interaction with HIV-infected DC, using an autologous in vitro NK/DC coculture system. We show that NK cell interaction with HIV-1-infected autologous monocyte-derived DC (MDDC) modulates NK receptor expression. In particular, expression of the CD85j receptor on NK cells was strongly down-regulated upon coculture with HIV-1-infected MDDC. We demonstrate that CD85j+ NK cells exert potent control of HIV-1 replication in single-round and productively HIV-1-infected MDDC, whereas CD85j− NK cells induce a modest and transient decrease of HIV-1 replication. HIV-1 suppression in MDCC by CD85j+ NK cells required cell-to-cell contact and did not appear mediated by cytotoxicity or by soluble factors. HIV-1 inhibition was abolished when NK-MDDC interaction through the CD85j receptor was blocked with a recombinant CD85j molecule, whereas inhibition was only slightly counteracted by blocking HLA class I molecules, which are known CD85j ligands. After masking HLA class I molecules with specific antibodies, a fraction of HIV-1 infected MDDC was still strongly stained by a recombinant CD85j protein. These results suggest that CD85j+ NK cell inhibition of HIV-1 replication in MDDC is mainly mediated by CD85j interaction with an unknown ligand (distinct from HLA class I molecules) preferentially expressed on HIV-1-infected MDDC.
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