Decker, S

Decker, S. 2G12 only. The envelope spike of human being immunodeficiency disease type 1 (HIV-1), a trimer of gp120/gp41 heterodimers, utilizes a number of strategies to avoid antibodies (Abs) elicited from the humoral immune response. These include variable loops, weighty glycosylation (36), conformational masking of important practical sites (19), and an architecture and surface denseness that reduce bivalent Ab engagement (18). However, a small number of broadly cross-reactive neutralizing Abs have been found and extensively characterized (5, 32, 41). The focuses on of these Abs include the membrane proximal region of gp41 (24, 42), a cluster of high-mannose carbohydrates on gp120 (29), and the HIV receptor (CD4)-binding site (3, 28). A combination of several of these Abs has been evaluated in medical trials like a passive immunotherapy to reduce viral rebound during an interruption of antiretroviral therapy (34). Several CD4-containing proteins have also been explored clinically as you can therapeutics for treating HIV-1: soluble CD4 (13, 16), a CD4-Fc fusion protein (7), and the tetravalent CD4-immunoglobulin G2 (CD4-IgG2; PRO 542) reagent (1, 17). In individuals with advanced disease, CD4-IgG2 treatment led to a 0.5 log10 mean reduction in viral load (17). In addition, D1D2-Igtp, an approximately dodecameric CD4 reagent produced like a chimeric IgG1/IgA fusion protein (2), exhibited very potent HIV neutralization activity and targeted HIV-infected cells for lysis by natural killer cells (14). Another approach to targeting gp120 is definitely a fusion protein composed of BINA CD4 linked to the variable regions of a CD4-induced (CD4i) Ab (11). CD4i Abs represent a potentially promising class of Abs because they bind to the conserved HIV-1 coreceptor binding site on gp120, which is definitely revealed after a conformational switch resulting from binding to CD4 (25, 27, 38). Examples of CD4i Abs include 17b (33), E51 (39), m9 (40), 412d (8), and 21c (38). These Abs are often broadly cross-reactive but generally display little neutralization potency in vivo due to limited steric convenience when gp120 within the viral membrane is bound to CD4 on the surface of the target cell (20). Fusing CD4 to the combining site of a CD4i Ab solves the convenience problem since the Ab epitope would be revealed by CD4 binding when the virion is not bound to the prospective cell. This class of reagent offers two other beneficial features: bivalent binding and focusing on of functionally essential epitopes on gp120, the CD4 BINA and coreceptor binding sites. One such reagent, sCD4-17b (referred to here as CD4-scFv17b), contains the 1st two domains of CD4 linked to the single-chain fragment variable BINA (scFv) form of the CD4i Ab 17b (Fig. ?(Fig.1)1) (11). This reagent was shown to potently neutralize multiple main strains of HIV-1 (11), suggesting that CD4-CD4i Ab fusion proteins BINA are encouraging candidates for passive immunization or gene therapy tests. Open in a separate windowpane FIG. 1. Schematic depiction of CD4-CD4i reagents and related molecules. VH, variable domain of the IgG weighty chain (HC); VL, variable domain of the IgG light chain LRP1 (LC), CH1, constant region 1 of the HC; CL, constant region of the LC; Fc, CH2 and CH3 domains of dimerized HCs; CD4 D1-D2, N-terminal two domains of CD4; scFv, single-chain fragment variable (VH and VL domains of an.