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TUPDA103

BIT225 Reduces the Intracellular HIV-1 Burden Within Monocyte Derived Dendritic Cells, Resulting in Reduced Transfer of Virus to more Permissive CD4 + T Cells J Wilkinson, G Ewart, C Luscombe and M Miller. Biotron Limited, Sydney, Australia.

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TUPDA103

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  1. BIT225 Reduces the Intracellular HIV-1 Burden Within Monocyte Derived Dendritic Cells, Resulting in Reduced Transfer of Virus to more Permissive CD4+ T CellsJ Wilkinson, G Ewart, C Luscombe and M Miller.Biotron Limited, Sydney, Australia Background: Specific viral proteins have ion channel activity (viroporins) led Biotron to develop a library of compounds targeting Vpu. BIT225 has completed both preclinical safety and toxicity studies and a phase I dose escalation study. A phase Ib has recently been completed in HCV+ patients with two successive trials planned in HCV and HIV-1 cohorts. In vitro, BIT225 demonstrates good activity in macrophages. (Khoury et al., Antimicrobial Agents and Chemotherapy. 2010) Aims:To extend our findings and determine the anti-HIV-1 efficacy of our lead compound, BIT225, on viral replication in MDDC and determine the potential activity of BIT225 on the inhibition of transfer of HIV-1 from this compartment to more permissive CD4+ T cells when co-cultured. TUPDA103

  2. Mucosal TissuesLymph Nodes HIV+ iDC mature DC CD4+ T cell DC and HIV-1 dissemination (2 phase transfer) ‘Trojan Horse’ Maturation & Migration ( `24 h) -CLRs +Adhesion +Activation Turville et al. Blood 103: 2170. 2004

  3. DMSO 600 BIT225 20 M 500 400 HIV-1 Replication by RT (U/mL) 300 200 100 0 Time (days) 0 1 2 4 5 6 7 8 9 10 11 12 3 13 14 BIT225 Inhibits HIV-1 Replication in MDDC Methods: Day 6, immature MDDC (CD1a+CD14-CD4+DC-SIGN+MR+CD83-) infected with HIVBaL and cultured ‘one shot’ dose of ±BIT225 (v DMSO) for 14 days • BIT225 resulted in 72% inhibition of HIV-1 replication in infected MDDC • Dose dependent response TUPDA103

  4. trans cis 100000 10000 1000 HIV-1 Replication in the 4 day co-culture (Log RTU/mL) 100 10 0 0.1 0.2 1 2 3 4 5 6 7 8 9 10 11 12 Age of Infected MDDC Sampled for 4 Day Co-culture (days) DMSO BIT225 20 uM BIT225 Reduces HIV-1 Transfer from MDDC to CD4+s Methods: At various time points, infected MDDC ±BIT225 were cultured with PHA activated CD4+ T cells (HIV-1 seronegative donors) at a ratio of 1:4 for 4 days of co-culture with no additional drug added • BIT225 resulted in 89% inhibition of HIV-1 transfer from MDDC to CD4+s • in cis only, supporting the role of BIT225 as a late stage viral inhibitor TUPDA103

  5. In Summary A single dose of BIT225 resulted in reduced: • HIV-1 replication in MDDC (72% inhibition out to day 14) • Transfer to T cells in co-culture (89% inhibition) • in cis only, supporting the role of BIT225 as a late stage viral inhibitor “BIT225 has the potential to decrease HIV-1 replication in infected dendritic cells. In these infected cells, BIT225 may also assist in reducing the dissemination of HIV-1 to more permissive host cells, as the HIV laden DC traffic from peripheral sites of infection to CD4+ T cell rich lymph nodes” TUPDA103

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