AEGiS-14IAC: In vitro effects of HIV infection on ABC transporter expression and antiretroviral drug efficacy.

14th International AIDS Conference

Barcelona, Spain - July 7-12, 2002

In vitro effects of HIV infection on ABC transporter expression and antiretroviral drug efficacy.

Int Conf AIDS 2002 Jul 7-12; 14:(abstract no. ThOrA1435)

Jorajuria S, Dereuddre-Bosquet N, Dormont D, Clayette P
CEA, fontenay-aux-roses, France

BACKGROUND: Intracellular concentrations of anti-HIV drugs are determinant for their pharmacological efficacy in peripheral blood as well as in sanctuary sites e.g. lymph nodes and CNS. ABC transporters such as P-glycoprotein (P-gp) and multidrug resistance-associated proteins (MRP) are reported to limit protease inhibitor (IP) and nucleoside reverse transcriptase inhibitor (NRTI) access to their cellular and tissular targets. Moreover, HIV may regulates the expression and activity of these host cell factors. Therefore, the present study aimed to evaluate in primary cultures of human monocyte-derived macrophages (MDM) and lymphocytes, effects 1) of retroviral infection and HAART on the expression and activity of P-gp and MRP and 2) of specific inhibitors of these host proteins on antiretroviral activities of NRTI, Non-NRTI and IP

METHODS: The mRNA expression of these different host cell factors were measured by RT-PCR, cell surface expression by flow cytometry, and activity using specific subtrates e.g. rhodamine.

RESULTS: On the one hand, we evidenced a transitory increase of P-gp mRNA expression in lymphocytes and MDM in response of in vitro HIV infection. This was correlated to an increased P-gp cell surface expression and activity, and an increased TNF-α and IL-6 production and mRNA. In contrast, no significant modulation of MRP was observed, and in parallel, treatments with AZT and indinavir do not influence the P-gp activity. On the other hand, PSC833 and probenecid potentiated in vitro the anti-HIV activity of AZT and indinavir. These effects were accentuated when PSC833 and probenecid were combined.

CONCLUSION: These results showed that 1) the HIV infection by increasing the ABC transporter expression could favorise the efflux of antiretroviral drugs and decrease their pharmacological effects, and 2) specific inhibitors of these transporters could reverse these deleterious effects.

Keywords: AEGIS, HIV Infections, Antiretroviral Therapy, Highly Active, Anti-HIV Agents, Reverse Transcriptase Inhibitors, Indinavir, Zidovudine, Multidrug Resistance-Associated Proteins, HIV Seropositivity, Lymphocytes, Human, In Vitro

020707
ThOrA1435