Freshly isolated human monocytes were labeled with Fluo-4 and then treated (indicated by the arrow) with either PBS alone (negative control), ionomycin (positive control), cross-linked CD4-specific monoclonal antibodies (XL-CD4 MAb), sMHC-II, or IL-16. contamination. Altogether, our studies have identified a novel function for Rolapitant the CD4 molecule on peripheral monocytes and suggest that a unique set of events that lead to innate immune activation differ between humans and mice. Further, these events can have effects on HIV Rolapitant contamination and persistence in the macrophage compartment. IMPORTANCE The CD4 molecule, as the primary receptor for HIV, plays an important role in HIV pathogenesis. There are numerous cell types that express CD4 other than the primary HIV target, the CD4+ T cell. Other than allowing HIV contamination, the role of the CD4 molecule on human monocytes or macrophages is not known. We were interested in determining Rolapitant the role of CD4 in human monocyte/macrophage development and function and the potential effects of this on HIV contamination. We identified a role for the CD4 molecule in triggering the activation and development of a monocyte into a macrophage following its ligation. Activation of the monocyte through the CD4 molecule in this manner increases the ability of monocytes to bind to and become infected with HIV. Our studies have identified a novel function for the CD4 molecule on peripheral monocytes in triggering macrophage development that has direct consequences for HIV contamination. INTRODUCTION Monocytes, which typically represent approximately 10% of human peripheral blood mononuclear cells (PBMCs), are mobile progenitor cells to tissue-embedded macrophages and dendritic cells (DC). Monocytes are a heterogeneous group of cells that are distinguished by the expression of Rolapitant several cell CORO2A surface molecules, including CD14, CD16, CD64, and CD4 (1, 2). Due to their expression of pattern recognition receptors, monocytes represent an immediate, nonproliferating effector populace of cells that play key functions in innate immunity through their inflammatory and phagocytic responses (3). Their primary functions include triggering antimicrobial responses, maintaining tissue homeostasis, performing tissue repair, and scavenging toxic or foreign material (1, 4). The ability of monocytes to produce a variety of proinflammatory cytokines following their activation and their ability to serve as antigen-presenting cells (APCs) bridge the innate immune response with the modulation of the adaptive immune response during inflammation (1). Importantly, peripheral monocytes rapidly differentiate into macrophages following activation with various immune signals, including Toll-like receptor (TLR) ligands, interleukin 10 (IL-10), and IL-15 (5,C7). These rapidly differentiated macrophages are characterized by their functional activities, including phagocytosis and antimicrobial activity, as well as their expression of CD209 (5,C7). One significant, unique aspect of human monocytes and macrophages, compared to mouse macrophages, is usually that they express the CD4 molecule (8). While the function of CD4 on T cells is Rolapitant usually well characterized, the function of CD4 on human monocytes is not well comprehended. The CD4 molecule is usually a 55- to 58-kDa membrane-bound glycoprotein member of the immunoglobulin family of receptors and interacts with major histocompatibility complex class II (MHC-II), IL-16, and human immunodeficiency computer virus (HIV) gp120 (9,C11). Neither the conversation of CD4 on non-T cells with MHC-II nor the signaling capability of CD4 in macrophage lineage cells is usually fully understood. For instance, while it is usually clear that this intracellular domain name of CD4 interacts with the Src family kinase Lck in T cells, CD4+ monocytes lack expression of Lck (9, 12). Macrophages are an important cellular target and viral reservoir for HIV in infected individuals (13). Besides HIV contamination of the CD4+ T helper cell populace, macrophages are thought to constitute the second most-infected cellular subset and the longest-lived one. Infected macrophages are found distributed in every tissue in the body in HIV-infected individuals (13,C16). Macrophages are believed to be important in the persistence and pathogenesis of HIV contamination due to their widespread anatomical presence and.