Assessing fusion/entry inhibitors in DC-T cell mixtures

Weill Medical College Of Cornell Univ, New York NY

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Abstract

Description (Provided by applicant): Dendritic c-ells (DCs), the immune system's most effective antigen presenting cells, have been (i) implicated, along with T cells, as one of the first cells targeted by HIV after mucosal exposure and (ii) shown to promote virus replication in concert with CD4+ T cells. Paralleling the human system, macaque DC- T cell mixtures were defined as a distinctive niche in which SIV can propagate in vitro and in vivo. Different subsets of DCs and T cells, and the type of virus can influence the level of virus growth. Furthermore, DCs express several molecules that are used by the virus for binding and entry. These include CD4, chemokine receptors, and DC- SIGN. Therefore, directly interfering with specific DC-virus interactions and transmission of virus between cells represents a promising anti-viral strategy that is of relevance to the development of mechanism-based microbicides. This proposal will focus on defining how putative attachment, fusion, and entry (AFE) inhibitors that target virus envelope interactions with CD4, DC-SIGN, or chemokine receptors impact DC-virus interplay and their ability to drive virus spread between cells in vitro, and whether the receptors involved are influenced by the DC subset. The questions being considered are: 1- Do APE inhibitors influence DC function? 2 - Can specific APE inhibitors block the binding, uptake, or transmission of SIV/HIV by DCs using a novel inactivated virus model? 3 - Which APE inhibitors effectively impede virus replication in the model blood DC- T cell system? 4 -Is infection of mucosal DC- T cell mixtures prevented by APE inhibitors? These studies will reveal critical details about how agents that prevent virus fusion and entry block DC-driven virus spread, a central event in establishing infection upon mucosal exposure. Identifying effective strategies to impede DC-virus interplay without impairing DC function is vital for the advancement of anti-HIV microbicidal approaches.