Infection with the human immunodeficiency virus (HIV-1) leads to a wide range of immunological abnormalities. We have shown that native envelope glycoproteins (gpl20) of HIV-1 inhibit antigen-specific and anti-CD3 induced lymphoproliferation of normal lymphocytes. We have demonstrated that gpl20 binds to CD4 positive T lymphocytes and is internalized. These studies suggest that interaction of gpl20 with the CD4 receptor may be sufficient to inhibit antigen-specific T cell responses that are mediated via the CD3-Ti receptor complex. Such an event could represent another mechanism by which the overall immune function of the CD4 positive T lymphocyte is depressed and may be relevant in planning investigations on the ongoing vaccine trial involving envelope glycoproteins.