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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. Wilkinson1, G. Ewart2, C. Luscombe2, M. Miller2

Background:
Dendritic cells (DC) are able to bind, uptake and disseminate HIV-1
during the very early stages of infection. HIV-1 exposed DC rapidly mature and migrate from the site of
infection to the lymph nodes (~24h) where they present HIV-1 to CD4+
T cells, resulting in explosive viral replication within the host. Our lead compound, BIT225 blocks Vpu
ion channel activity and demonstrates strong anti-HIV-1 activity in human
macrophages. Here we further
define the extent of BIT225 antiviral activity in relation to HIV-1BaL
infected monocyte-derived DC (MDDC).


Methods: Day 6
MDDC were infected with HIV-1BaL at MOI of 0.05 and cultured alone and
with uninfected, PHA-activated, heterologous CD4+ T cells at
specific time points (0-168h) and co-cultured for an additional 7 days ±BIT225.
HIV-1 was quantified in the MDDC cultures and MDDC-CD4+
co-cultures with the difference an estimate of HIV-1 transfer.


Results: BIT225
treatment post-infection resulted in a lower virus burden within the infected
MDDC as measured by reduced virus transfer in trans (< 24 h) and additionally a reduced transfer of de
novo virus in cis compared to DMSO treated controls. This effect was dose dependent, with
BIT225 at the highest dose of 20 uM resulting in 80% less transfer of virus in trans and >90% inhibition during the cis phase of transfer.


Conclusions: BIT225
resulted in reduced transfer of HIV-1 to activated T cells in both trans and cis
with no cellular toxicity. BIT225
may induce a more hostile environment within the intracellular compartments
facilitating increased endolysosomal degradation or viral assembly as we have
previously reported in BIT225 treated macrophages. We are currently attempting to confirm this possibility
using electron and confocal microscopy.
Therapies able to limit the dissemination of HIV-1 by DC to more
permissive host cells at very early stages of infection could be of great
clinical value.




AIDS 2010 - XVIII International AIDS Conference
Abstract no. TUPDA103

Suggested Citation
"J.Wilkinson, et al. BIT225 reduces the intracellular HIV-1 burden within monocyte derived dendritic cells resulting in reduced transfer of virus to more permissive CD4+ T-cells. : AIDS 2010 - XVIII International AIDS Conference: Abstract no. TUPDA103