This study shows that specific chemical inhibitors directed against the EPS motif or CRD domain of DCIR GDC-0449 prevent the attachment of HIV-1 to DCs and to apoptotic or infected CD4TL, without any side effect on CD4TL proliferation. Our DCIR homology model, in addition to providing detailed structural information, will help in the development of new lead compounds using virtual screening combined with in vivo testing. It was also crucial to determine the impact of these inhibitors on cellular viability. Peripheral blood mononuclear cells were pre-incubated with the inhibitors before measuring mitogenic stimulation and cellular proliferation using the MTT method. Figure 4 shows clearly that the inhibitors did not affect cell proliferation and that the observed, for all cell lines or primary cells used in this study, decrease in HIV-1 binding induced by these compounds resulted from ICI 182780 disrupted interaction with DCIR and was not a mere consequence of reduced viability. Dose response was also performed and toxicity was observed for concentration over 50 mM for all four inhibitors. Potential side effects of these inhibitors on cells expressing a large amount of DCIR was tested, and the results show that neutrophil functional response such as de-granulation was not affected by these inhibitors. This observation strengthens the conclusion that these inhibitors seem specific and not toxic. Finally, the impact of the inhibitors on the expression HIV-1 receptor CD4 or co-receptors CCR-5 and CXCR4 on DCs was assessed by cytofluorometry and their expression was not affected by inhibitors pre-treatment. Despite great strides in our understanding of HIV-1 pathogenesis and immune protection, the pandemic keeps expanding while no effective cure appears likely to become available in the near future. Moreover, the anti-HIV-1 drugs developed so far promote the selection of resistant strains of the virus. The introduction of antiretroviral therapy in the mid 1990s had a strong impact on the course of HIV-1 infection throughout the world. Currently available treatments target different steps of the viral propagation cycle, such as entry into the host cell, reverse transcription, integration and protein maturation. These have led to significant reductions in HIV-related mortality. Although combinations of antiretroviral drugs, such as HAART therapy, first met with resounding success, their limitations soon became obvious. Patient morbidity is enhanced and drug-resistant viruses have emerged, while no current antiretroviral therapy actually eradicates the virus from the body. Based on the major role played by DCIR in HIV-1 infection, we provide novel strategies to block HIV-1 transmission by DCs as well as by apoptotic or HIV-1-infected CD4TL. In this study, a detailed three-dimensional structure of DCIR has been proposed and four inhibitors directed against the CRD domain and EPS motif of DCIR blocking HIV-1 replication and propagation have been identified.