It is now clear that HIV and SIV have evolved specific strategies to evade host immune responses and that these immune evasion strategies allow continuous, unrelenting viral replication. Antibodies that can neutralize viral infectivity are directed to the viral-encoded envelope proteins, gp120 and gp41. These proteins are responsible for binding of virus to receptors on the cell surface and for mediating entry by fusion with host cell membranes. Two specific features of the gp41 transmembrane protein of HIV and SIV will be investigated for their contributions to viral replication and immune evasion; the role of carbohydrates on the ectodomain and the binding of the cytoplasmic tail to specific cellular partners. The effects of carbohydrate on gp41 on antigenicity (ability to be recognized by antibodies capable of neutralizing viral infectivity) and immunogenicity (ability to elicit antibodies capable of neutralizing viral infectivity) will be thoroughly documented. The relative importance and functional contribution of binding of the cytoplasmic domain of gp41 to a newly-identified cellular partner will be investigated. These studies are important at a fundamental level for better understanding of the mechanisms of viral replication, immune evasion, and pathogenesis. Better understanding of these parameters will eventually fuel vaccine and drug development efforts.