This suggests that unlike the soluble D1D2 protein, the D1D2 domains in 2DLT may not be able to replace CD4 on cell surface to drive HIV-1 infection in the CD4-/CCR5+ cells or the rapid decay of the gp41 fusion-intermediate mediated by 2DLT results in the abolishment of the potential enhancement of HIV-1 infection. Here, CD4 is linked to HIV-1 infection.