Fusion Proteins as HIV-1 Entry Inhibitors

Soluble forms of human CD4 (sCD4) inhibit HIV-1 entry into immune cells.  Different forms of sCD4 and their fusion proteins have been extensively studied as promising HIV-1 inhibitors – including in animal models and clinical trials.  However, they have not been successful in human studies due to their transient efficacy.  sCD4 is also known to interact with class II major histocompatibility complex (MHCII) and, at low concentrations, could enhance HIV-1 infectivity. 

NCI researchers previously described a novel bispecific multivalent fusion protein called 4Dm2m which contains a single human CD4 domain (mD1.22) and a potent HIV-1 inhibitor (m36.4) (NIH Reference No. E-033-2013).  mD1.22 is highly soluble and stable with good neutralizing activity without measurable interaction with MHCII.  The NCI inventors have recently discovered new variants of 4Dm2m with increased stability and potency in mediating antibody dependent cellular cytotoxicity (ADCC) against cells expressing the HIV-1 envelope glycoprotein.  The newly identified variants also have increased half-lives in vivo and enhanced antibody binding.