Human dendritic cells (DCs) are classified into three subsets based on their ontogeny, transcriptomes, and functions. During primary human immunodeficiency virus (HIV) infection, DCs in the peripheral tissues capture the HIV-1 particles, migrate to the lymph nodes, transfer the particles to CD4(+) T cells, and initiate infection. However, the identity of the DC subset involved is yet elusive. Hitherto, a novel subset (AXL(+)DCs) has been identified in human blood, which is transcriptomically and functionally distinct from three known subsets. Compared to these, resting AXL(+)DCs express Siglec1 (CD169), capture HIV-1 particles in a CD169-dependent manner, and mediate transinfection. These results suggested that AXL(+) DCs may facilitate HIV-1 transmission and the spread of very early-stage HIV infection in patients. Therapeutic strategies that target AXL(+)DCs or CD169 interaction with HIV-1 may provide pre-exposure protection during the initial stages of HIV-1 infection.