ANTIVIRAL EFFECTS OF DIFFERENT CD4-IMMUNOGLOBULIN CONSTRUCTS AGAINST HIV-1 AND SIV - IMMUNOLOGICAL CHARACTERIZATION, PHARMACOKINETIC DATA AND INVIVO EXPERIMENTS

The CD4 cell surface antigen belongs to the immunoglobulin superfamily and is the primary receptor for the human immunodeficiency virus 1 (H IV-1). The high affinity interaction between HIV-1 and CD4 is mediated by the viral envelope glycoprotein gp120. Recombinant soluble CD4 (rs CD4) has been shown in vitro to be an effective inhibitor of HIV-1 and HIV-2 propagation in lymphoid cells. A variety of antibody-like molec ules were constructed, consisting of different parts of the extracellu lar domain of CD4 fused to immunoglobulin constant regions. The fusion proteins were expressed in mammalian cell lines and purified via affi nity chromatography. The specificity and anti-viral effects of the dif ferent CD4-immunoglobulin constructs against HIV were analysed by diff erent immunological tests, i.e., immunofluorescence, neutralisation an d in vitro assays. In pharmacokinetic studies, differences were found in serum half-life between the four- and two-domain CD4 constructs in cynomolgus monkeys and between glycosylated and deglycosylated CD4-Fc constructs in rabbits. In two in vivo experiments using the four-domai n CD4-Fc in SIV-infected macaques, no beneficial effects were observed .