Abstract
The HIV-1 pandemic continues to expand while no effective vaccine or cure is yet available. Existing therapies have managed to limit mortality and control viral proliferation, but are associated with side effects, do not cure the disease and are subject to development of resistance. Finding new therapeutic targets and drugs is therefore crucial. We have previously shown that the dendritic cell immunoreceptor (DCIR), a C-type lectin receptor expressed on dendritic cells (DCs), acts as an attachment factor for HIV-1 to DCs and contributes to HIV-1 transmission to CD4+ T lymphocytes (CD4TL). Directly involved in HIV-1 infection, DCIR is expressed in apoptotic or infected CD4TL and promotes trans-infection to bystander cells. Here we report the 3D modelling of the extracellular domain of DCIR. Based on this structure, two surface accessible pockets containing the carbohydrate recognition domain and the EPS binding motif, respectively, were targeted for screening of chemicals that will disrupt normal interaction with HIV-1 particle. Preliminary screening using Raji-CD4-DCIR cells allowed identification of two inhibitors that decreased HIV-1 attachment and propagation. The impact of these inhibitors on infection of DCs and CD4TL was evaluated as well. The results of this study thus identify novel molecules capable of blocking HIV-1 transmission by DCs and CD4TL.
Highlights
The discovery of new therapeutic targets and the development of new therapeutic approaches are necessary in order to pursue the fight against human immunodeficiency virus type 1 (HIV-1)
We have recently demonstrated that the C-type lectin receptor known as dendritic cell immunoreceptor or DCIR [16] allows HIV-1 to attach to dendritic cells (DCs) and enhances HIV-1 infection in both phases [17], unlike DC-SIGN, which is only involved in the early phase [18,19]
We have shown, using antibodies directed against the EPS motif or carbohydrate recognition domain (CRD) domain, or by deleting the neck domain, that these extracellular portions are both involved in the binding of HIV-1 and its subsequent transfer to CD4+ T lymphocytes (CD4TL) [17]
Summary
The discovery of new therapeutic targets and the development of new therapeutic approaches are necessary in order to pursue the fight against human immunodeficiency virus type 1 (HIV-1). The drugs currently available or in development for treating HIV-1 infection target the virus itself and its replication mechanisms and risk selecting resistant variants. These treatments increase the lifespan of patients, they contribute to increased co-morbidity [1]. Studies of a simian model and more recently of human HIV-1 show that treatment during the acute phase of infection improves the immune response to the virus [2,3]. It has been demonstrated that early events in HIV-1 infection are highly determinant in the irreversible damage inflicted to key immune cells [3,4,5,6,7]. To maintain vital immune competency, it is crucial to find new targets involved in the first steps of viral transmission and prevent the devastating initial damage to the immune system
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