Coinfections of human immunodeficiency virus (HIV), EBV, and HTLV or sperm proteins act synergistically to enhance infectivity and replication and expand cellular tropism. While some aspects of these synergisms are understood, others are not. We have found that membrane or surface proteins of CMV, HTLV, EBV and sperm proteins share large regions of similarity with the CD4 protein of T-helper lymphocytes. Since HIV uses CD4 as a receptor, it may bind to CD4 homologues on CMV, HTLV, EBV or sperm proteins. HIV could then "piggyback" with these viruses into cells with which it normally has no tropism. Similarly, HIV may expand the cellular tropism of CMV, or EBV. Such a piggyback mechanism may provide insight into the formation or presentation of CD4-like antigens from CMV, HTLV, EBV and sperm proteins with class II MHC-like antigens on HIV (gp160 and Nef proteins) and may break immunological tolerance, inducing the autoimmunity observed against both CD4+ and class II MHC+ T cells in AIDS patients.