OBJECTIVES:: To determine the effect of IgG2 opsonization on internalization of HIV-1 virus-like particles (VLPs) by monocytes and to determine the effect of gp120 glycosylation on IgG subclass binding. DESIGN:: Fc-Fcγ receptor (FcγR) interactions are important in antibody-mediated protection from lentivirus infection. Such interactions are influenced by IgG subclass, with IgG2 having low affinity to most FcγRs. We determined the impact of IgG2 on internalization of antibody-opsonized VLPs. It is also known that gp120 glycans affect the binding and function of anti-gp120 antibodies. We determined whether binding of each IgG subclass to recombinant gp120 (rgp120) was similarly impacted by gp120 glycosylation. METHODS:: Green fluorescent protein (GFP) containing VLPs were opsonized with IgG and IgG2-depleted IgG from individuals vaccinated with rgp120 during the Vax004 vaccine trial. Opsonized VLPs were incubated with peripheral blood mononuclear cells from healthy donors (n = 46), and percentages of GFP+ monocytes were determined by flow cytometry. IgG subclass binding of pooled and individual sera to rgp120 and to deglycosylated (PNGase-treated) rgp120 was determined by ELISA. RESULTS:: IgG2 elicited by rgp120 vaccination inhibited internalization of antibody-opsonized HIV-1 VLPs by monocytes from healthy individuals (P = 2.8 × 10). We also found that both IgG2 and IgG4 bound more poorly to enzymatically deglycosylated rgp120 than to unchanged rgp120. On the contrary, IgG1 and IgG3 bound slightly better to deglycosylated rgp120. CONCLUSION:: Vaccine-induced IgG2 may adversely affect a potentially important antiviral antibody activity, and altering Env glycans might provide the means to bias the subclass response in a favorable direction. © 2011 Wolters Kluwer Health Lippincott Williams & Wilkins.