We have previously shown that FLSC, a chimeric protein containing HIV-1BAL gp120 and the D1 and D2 domains of human CD4 blocks binding and entry of HIV-1 into target cells by occluding CCR5, the major HIV-1 co-receptor. In an effort to improve the antiviral potential of FLSC, we fused it with the hinge-CH2-CH3 region of human IgG1. The IgG moiety should increase both the affinity and stability in vivo of FLSC, due to the resultant bivalency and in extended serum half-life, thereby increasing its antiviral potency. We previously showed that (FLSC) IgG1 indeed had greater antiviral activity against T cell infections. Here we extend these results to macrophages, in which (FLSC) IgG1 has a higher binding affinity and more potent antiviral activity in macrophages than FLSC alone. We also test both compounds in a relevant humanized mouse model and show that, as anticipated, the IgG1 moiety confers a greatly extended half-life. These data, taken together with previous results, suggest potential clinical utility for (FLSC) IgG1 with a prolonged half-life and support further developmental work toward eventual clinical trials.