CD4 Ligation on Human Blood Monocytes Triggers Macrophage Differentiation and Enhances HIV Infection

A unique aspect of humanmonocytes, compared to monocytes frommany other species, is that they express the CD4molecule. However, the role of the CD4molecule in humanmonocyte development and function is not known.We determined that the activation of CD4 via interaction with major histocompatibility complex class II (MHC-II) triggers cytokine expression and the differentiation of humanmonocytes into functional mature macrophages. Importantly, we determined that CD4 activation in-duces intracellular signaling in monocytes and that inhibition of the MAPK and Src family kinase pathways blocked the ability of CD4 ligation to trigger macrophage differentiation. We observed that ligation of CD4 byMHC-II on activated endothelial cells induced CD4-mediated macrophage differentiation of bloodmonocytes. Finally, CD4 ligation byMHC-II increases the sus-ceptibility of blood-derived monocytes to HIV binding and subsequent infection. Altogether, our studies have identified a novel function for the CD4molecule on peripheral monocytes and suggest that a unique set of events that lead to innate immune acti-vation differ between humans andmice. Further, these events can have effects on HIV infection and persistence in the macro-phage compartment. IMPORTANCE The CD4molecule, as the primary receptor for HIV, plays an important role in HIV pathogenesis. There are many cell types that express CD4 other than the primary HIV target, the CD4 T cell. Other than allowing HIV infection, the role of the CD4mole