Immunoglobulin G3 from polyclonal human immunodeficiency virus (HIV) immune globulin is more potent than other subclasses in neutralizing HIV type 1

Passive antibody prophylaxis against human immunodeficiency virus type 1 (H IV-1) has been accomplished in primates, suggesting that this strategy may prove useful in humans. While antibody specificity is crucial for neutraliz ation, other antibody characteristics, such as subclass, have not been expl ored. Our objective was to compare the efficiencies of immunoglobulin G (Ig G) subclasses from polyclonal human HIV immune globulin (HMG) in the neutra lization of HIV-1 strains differing in coreceptor tropism. IgG1, IgG2, and IgG3 were enriched from HIVIG by using protein A-Sepharose, All three subcl asses bound major HIV-1 proteins, as shown by Western blot assay and enzyme -linked immunosorbent assay. In HIV-1 fusion assays using X4, R5, or X4R5 e nvelope-expressing effector cells, IgG3 more efficiently blocked fusion, In neutralization assays with cell-free viruses using X4 (W, IIIB), R5 (BaL), and X4R5 (DH123), a similar hierarchy of neutralization was found: IgG3 > IgG1 > IgG2. IgG3 has a longer, more flexible hinge region than the other s ubclasses. To test whether this is important, IgG1 and IgG3 were digested w ith pepsin to generate F(ab '), fragments or with papain to generate Fab fr agments. IgG3(ab '), fragments were still more efficient in neutralization than F(ab '), of IgG1. However, Fab fragments of IgG3 and IgG1 demonstrated equivalent neutralization capacities and the IgG3 advantage was lost. Thes e results suggest that the IgG3 hinge region confers enhanced HIV-neutraliz ing ability. Enrichment and stabilization of IgG3 may therefore lead to imp roved HIVIG preparations. The results of this study have implications for t he improvement of passive immunization with polyclonal or monoclonal antibo dies and suggest that HIV-1 vaccines which induce high-titer IgG3 responses could be advantageous.