AEGiS-15IAC: Signal transduction pathway involved in HIV-induced ABC transporter overexpression and subsequent mechanisms in the limitation of AZT antiretroviral efficacy.

15th International AIDS Conference

Bangkok, Thailand - July 11-16, 2004

Signal transduction pathway involved in HIV-induced ABC transporter overexpression and subsequent mechanisms in the limitation of AZT antiretroviral efficacy.

Int Conf AIDS 2004 Jul 11-16; 15:(abstract no. WeOrA1275)

Jorajuria S, Dereuddre-Bosquet N, Martin S, Orlowski S, Dormont D, Clayette P
Service de Neurovirologie, CEA, CRSSA, EPHE, Fontenay-aux-Roses, France

BACKGROUND: ABC transporters, such as P-gp and MRP, are efflux pumps that limit the access of anti-HIV drugs to their cell and tissue targets. We previously showed in human macrophages (MDM), that 1) HIV infection transiently upregulates P-gp activity at the transcriptional level in parallel of TNF-ialpha production, and 2) the inhibition of P-gp and MRP activities increased the anti-HIV efficacy of AZT. Herein we 1) extended the study to MRP expression, 2) analyzed the intracellular pathways involved in HIV-induced overexpression of these transporters, and 3) investigated the mechanisms that underlie the increase in AZT activity after P-gp and MRP inhibition.

METHODS: The mRNA expression of these different cell factors were measured in HIV-infected MDM by RT-PCR. P-gp ATPase activity was measured in response to AZT or its metabolites in "inside out membrane" vesicles overexpressing P-gp.

RESULTS: On the one hand, we evidenced that MRP4, like P-gp, was significantly increased by HIV infection, whereas levels of MRP1 and MRP5 mRNA were increased during HIV replication. On the other hand, we showed that the upregulation of P-gp, consecutively to HIV infection, was dependent on virus tropism and was reversed by inhibitors of gp-120/CD4 binding and fusion and of protein kinase C and NF-kappaB pathways. Finally, we demonstrated that nor AZT, nor its derivatives interacted directly with P-gp. Conclusion These results showed that ABC transporters are sequentially overexpressed in HIV-infected MDM. P-gp and MRP4 are expressed soon after infection, subsequently to gp120/CD4/CCR5 interactions and TNF-ialpha release by MDM. MRP1 and MRP5 are expressed concomitantly to HIV replicative phase suggesting another regulation mechanism. Lastly, during MDM infection, MRP5 takes over from MRP4 for AZT efflux. Altogether, these data explain how HIV infection, by increasing the ABC transporter expression, could favorise the efflux of antiretrovirals and decrease their efficacy.

Keywords: AEGIS, HIV, Acquired Immunodeficiency Syndrome, HIV Seropositivity, Zidovudine, Tumor Necrosis Factors, ATP-Binding Cassette Transporters, HIV Infections, Multidrug Resistance-Associated Proteins, Genes, MDR, cdc42 GTP-Binding Protein, Antigens, CD4, Signal Transduction, Virus Replication, HIV Protease Inhibitors, Humans, genetics, immunology, virology

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