Viral entry to the CD4+ cell begins with attachment of the R5 HIV-1 glycoprotein 120 (gp120) to the CD4+ T-cell receptor, which produces a conformational change in gp120 and allows it to bind to CCR5, thereby triggering glycoprotein 41 (gp41) mediated fusion of the viral envelope with the cell membrane and the nucleocapsid enters the host cell (Figure 1). CCR5 co-receptor antagonists prevent HIV-1 from entering and infecting immune cells by blocking CCR5 cell-surface receptor. Small molecule antagonists of CCR5 bind to a hydrophobic pocket formed by the transmembrane helices of the CCR5 receptor. They are thought to interact with the receptor in an allosteric manner locking the receptor in a conformation that prohibits its co-receptor function. As mentioned, the CCR5 receptor is a G-protein coupled receptor (GPCR). Before the discovery of CCR5's role in HIV infection, many pharmaceutical companies had already built a substantial collection of compounds that target GPCRs. Some of these compounds would prove to be a starting point for CCR5 antagonist medicinal chemistry, but would need optimization to improve CCR5 selectivity and potency, and to improve pharmacokinetic properties. A significant problem was the affinity of available screening hits for the hERG ion channel; inhibition of hERG leads to QT interval prolongation, which can increase the risk of developing fatal ventricular arrhythmias. Many CCR5 antagonists have been studied by pharmaceutical companies, but few of them have actually reached human efficacy studies; for example AstraZeneca, Novartis, Merck, and Takeda have used their GPRC-targeting compound collections to develop a potent CCR5 antagonist, but none of them have reached clinical trials. Three pharmaceutical companies were in competition to be the first to have a small molecule CCR5 antagonist approved: GlaxoSmithKline (GSK) with their compound aplaviroc, Schering-Plough with vicriviroc, and Pfizer with maraviroc. All of the compounds reached clinical trials in humans; only maraviroc has been approved by the U.S. Food and Drug Administration (FDA). CytoDyn's CCR5 antagonist leronlimab (PRO 140) will potentially be approved in the first quarter of 2020 after the full submission of their BLA in September/October 2019.