Issn Print: 0269-9370

Publication Date: 2000/07/07


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Increased β-chemokine production in peripheral blood mononuclear cells derived from HIV-1-infected individuals by a cationic amphiphilic drug (AY 9944) in vitro

Ammar Achour

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Chemokines are chemottractant cytokines induced by inflammatory stimuli, which play a crucial role in leukocyte migration and T cell activation [1]. A series of papers [2–4] has reported that macrophage inflammatory proteins (MIP)-1α, MIP-1β and regulated upon activation: normal T cell expressed/secreted (RANTES) β-chemokines inhibit the infection of T cells by macrophage-tropic HIV-1 strains. Studies [2,5] have reported that elevated levels of β-chemokines, which inhibit macrophage or dual tropic HIV-1 variants, were produced at higher levels in certain uninfected high-risk individuals. All three chemokines were produced by both T cells at the highest level after activation (72 h). By days 5–7 after stimulation, the levels of chemokines decreased significantly and then rose slowly over 9 days of culture [6].
In a previous report [7] it was reported that AY 9944 [trans-1,4-bis (chlorobenzylaminomethyl)-cyclohexan dihydrochloride], an inhibitor of sterol synthesis, was found to restore the cell survival and cytokine profile of peripheral blood mononuclear cells (PBMC) after 15 days of culture in vitro. In order to evaluate whether AY 9944 could stimulate the expression of β-chemokines, the action of the drug on chemokine production was assessed in cultured naturally infected PBMC of five AIDS patients (CD4 T cell count < 200/mm3). For this purpose, experiments were designed in which PBMC were activated with phytohaemagglutinin and cultured with IL-2 supplemented complete medium in the presence or absence of AY 9944 (3.10−6 M) (Sigma–Aldrich, Milwaukee, USA) as described [7]. Fifteen days after phytohaemagglutinin stimulation, PBMC cultured in complete medium in the presence of AY 9944 exhibited a seven- to 40-fold increase in the mean levels of MIP-1α, MIP-1β and RANTES produced compared with control cells (Table 1). This production was maintained at a high level during the 4 weeks of culture. Although the mean levels of β-chemokines were significantly higher by activated PBMC cultured in the presence of the drug (P  < 0.001), these levels (1500–28 000 pg/ml) are in accordance with the range required to block infection with some HIV isolates in vitro[2]. It is accepted that MIP-1α, MIP-1β and RANTES play a beneficial role in the early phases of HIV infection in vivo by inhibiting macrophage tropic HIV-1 strains, and the CCR-5 co-receptor plays a major role in HIV infection. Because the isolation of HIV-1 for primary cultures was not systematically carried out, in the study no virus production was observed in untreated or AY 9944-treated cells. Further experiments are needed to investigate the capacity of resistance of treated cells to infection with primary isolates of HIV-1 [5,7]. To our knowledge, this is the first report indicating that the production of MIP-1α, MIP-1β and RANTES β-chemokines was enhanced in PBMC derived from HIV-1-infected individuals after the in-vitro action of a chemical compound.
This finding suggests that AY 9944 and derived molecules may represent important candidates for therapies based on enhancing the level of resistance to HIV infection.

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