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The regulatory Tax protein of HTLV-1 (Human T-cell Leukaemia Virus type 1) is critically involved in the initiation of ATL (adult T-cell leukaemia). Indeed, Tax provides infected T-cells with a growth advantage and with the potential to get transformed through the deregulation of cell-cycle progression and the acquisition of genetic alterations. Considering that leukemias are induced by disturbances in hematopoietic cells development, we hypothesize that the expression of Tax in human immature thymocytes is a prerequisite to the emergence of ATL cells. Studies of alph abeta T-cell development in the thymus have shown that beta-selection, an early important checkpoint, is regulated by transcription factors that are decisive in the control of cell proliferation, differentiation and survival. Interestingly, Tax is endowed with the ability to interfere with the activity of these transcription factors. We therefore propose that the HTLV-1 infection of these specific target thymocytes leads to a transcriptional deregulation of early alphabeta T cell development, thus inducing a pre-leukemogenic event that favours the subsequent proliferation of ATL cells.

An IL-2 autocrine growth circuit has been proposed as a major mechanism in HTLV-I-related leukaemogenesis. We have developed a polymerase chain reaction combined with reverse transcription RT-PCR to detect IL-2 transcripts and a sensitive immunostaining method for IL-2 protein. Combination of these two methods with in situ hybridization demonstrated that most cells of the T cell line IARC 301.5, whose proliferation is stimulated by autocrine IL-2, constitutively synthesize IL-2. This pattern was also found in the HTLV-I T cell lines HUT, MT2 and C 8166/45, and in the HTLV-I-negative T cell lines Jurkat and HSB2 but not MOLT4. Four non-lymphoid cell lines and cultured fibroblasts were negative, in agreement with the T cell specificity of IL-2 synthesis. Hence, most T cell lines tested, whether HTLV-I-infected or not, constitutively synthesize IL-2, suggesting a possible common feature of leukaemic T cell lines. The presence of IL-2 transcript and protein in most cells of the reacting cell lines is consistent with an autocrine process possibly involved at some stage in acquiring growth autonomy.

International audience

Sera from 182 Zairians (99 females and 83 males), aged 5 to 71 years, including maternity and child care consultants, out-patients suffering from minor injuries and patients hospitalized for tuberculosis, malaria or trauma, were analyzed for specific antibodies to HTLV-I and HTLV-III. Following pre-screening by the ELISA technique, reactive sera were further analyzed for specificity to HTLV-I or HTLV-III antigens by competition and/or Western blotting experiments. African sera, possibly because they have higher immunoglobulin levels than US and European sera, are highly reactive in ELISA systems and confirmatory assays are essential to rule out false-positive results. Confirmed antibody prevalence for HTLV-I was 13.2% (II females and 13 males) and increased with age, suggesting continuous exposure to the virus throughout life. Confirmed antibody prevalence for HTLV-III was 6.0% (8 females and 3 males) and showed a peak age range between 21 and 40 years, suggesting heterosexual transmission. Individuals positive for HTLV-I antibodies were not the same as individuals positive for HTLV-III antibodies, suggesting that infection with one virus did not increase susceptibility to infection by the other virus. Further investigations of the epidemiology and of the immunovirology of HTLV-III in Zaire, in relation to acquired immuno-deficiency syndrome (AIDS)-associated pathologies, should enlighten the question of the significant percentage of HTLV-III-infected individuals who do not manifest symptoms of AIDS.

When hyposialylated , immunoglobulins become immunogenic and tend to form aggregates. In pursuit of the possibility that hyposialylated immunoglobulins (hs-Ig) can trigger human mononuclear phagocytic cells, we have investigated the effects of such hs-Ig on the myeloperoxidase (MPO) activity of these cells. The incubation of human monocytes with aggregated hs-Ig leads to the decrease of intracellular MPO activity. This decrease is dependent on the incubation time, on the amount of hs-Ig added, and on the degree of aggregation. Incubation with unaggregated hs-Ig has a similar effect, thus providing evidence that the loss of sialic acid residues per se is enough to render these molecules capable of decreasing the MPO content of phagocytic cells. Furthermore, human rheumatoid factors, isolated from the sera of rheumatoid arthritis patients, and previously characterized as hyposailylated Ig, interact in the same way with monocytes in triggering the MPO decrease. These observations imply that hs-Ig may be considered as active stimuli in the induction of inflammatory processes, through the initiation of oxidative reactions.

Cells of the monocyte lineage act as a major reservoir for HIV, and ways of enhancing the resistance of mononuclear phagocytes to HIV replication would be useful for delaying the onset of AIDS in infected individuals. Seif et al. (J. Virol. 65:664, 1991) have recently shown the possibility of obtaining stable antiviral expression (SAVE), directed against three nonretroviral RNA viruses, and normal cell viability in a significant percentage of murine BALB/c 3T3 cells transformed with an IFN-beta expression plasmid under the control of the 0.6-kb XhoII-NruI promoter region of the murine H-2Kb MHC gene. In the present paper, we show that it is possible to establish SAVE in human promonocytic cells. Cells of the human promonocytic U937 line were stably transfected with a human IFN-beta expression plasmid carrying the neo- and human IFN-beta-coding sequences under the control of the H-2Kb promoter fragment previously used in murine cells. After selection with G418, two transformed clones were isolated that released small amounts of human IFN-beta into the culture medium, without affecting the expression of CD4 and leucocyte function-associated Ag-1 differentiation Ag. The presence of construct-derived IFN-beta mRNA was demonstrated by polymerase chain reaction amplification of cDNA, and the level of 2-5A synthetase, one of the major IFN-induced antiviral proteins, was shown to be constitutively increased. These clones were less permissive for HIV-1 than control clones transformed with the neo gene only. The antiviral state could be modulated by anti-IFN-beta antibodies, in that the continuous presence of antibodies in the culture medium abolished the enhanced resistance to HIV-1 replication, whereas the withdrawal of the antiserum restored the antiviral state, indicating that it did indeed result from the constitutive synthesis of human IFN-beta. These results demonstrate the possibility of restricting HIV-1 replication in human promonocytic cells by establishing SAVE. Further exploration of this method as a possible approach to somatic cell gene therapy of HIV infection appears worthwhile.