Thus, the lack of correlation among Region III binding modes, SPR study, and viral infectivity led us to speculate that the undesired enhancement of CD4-independent HIV-1 infection may instead be modulated by interactions between Region III of the small molecule and gp120 that alter the conformations of variable loop elements in the viral spike, which were not revealed in the structures in the current study. Here, ITIH4 is linked to HIV-1 infection.