A major goal of HIV-1 research is the development of nontoxic agents that target novel stages of the viral replicative cycle, such as viral entry. New agents are needed both to combat the growing incidence of HIV-1 strains that are broadly resistant to existing antiretroviral medications and to lessen the considerable toxicities associated with current therapies. In addition, adequate control of HIV-1 replication generally requires uninterrupted, combination use of three or more drugs, mandating that new antiviral agents be produced as cost-effectively as possible in order to maximize patient access. CD4-IgG2 is a novel, tetravalent antibody-like molecule that incorporates four copies of the virus binding domains of human CD4, which is the primary receptor for HIV-1. CD4-IgG2 binds to the HIV-1 envelope glycoprotein gp120 with nanomoIar affinity, thereby preventing attachment of HIV-1 to target cells and viral entry. CD4-IgG2 has demonstrated potent activity against primary HIV-1 isolates in extensive preclinical testing and more recently in Phase I/II human clinical trials. CD4-IgG2 is the only HIV-1 attachment inhibitor in advanced clinical development and thus represents a new class of antiviral agent. CD4-IgG2 is potently synergistic when used in combination with agents that block other stages of viral entry, such as the gp41 fusion inhibitor T-20 and coreceptor-targeting agents. This result suggests that combinations of entry inhibitors could emerge as an important new treatment paradigm. CD4-IgG2 is currently produced via conventional cell culture methods. However, transgenic technology provides an unsurpassed method for low-cost, high-volume manufacture of complex biopharmaceuticals. The Phase I study demonstrated that biologically active CD4-IgG2 can be expressed at high levels in the milk of transgenic animals, using mice as a model system. The overall goal of the Phase II project is to produce CD4-IgG2 in the milk of transgenic dairy animals, and to determine the therapeutic potential of transgenic CD4-IgG2 in both the best available preclinical models of HIV-1 infection and in human clinical testing. Success in the project would represent an important milestone for the development both of a new class of anti-HIV-1 therapy and of transgenic technology.