Retroviruses induce in the infected host an immunosuppression the severity of which depends on the viral load. A pronounced immunosuppression is induced by human and simian immunodeficiency viruses (HIV and SIV) ultimately leading to AIDS. It is very likely that HIV originated by trans-species transmission from primates. In contrast, SIVs are not pathogenic for their natural hosts probably as the result of virus-host coevolution. We have shown that a retroviral protein, the transmembrane envelope protein, may play an important role in retrovirus-induced immunosuppression and that all retroviruses share an evolutionarily highly conserved domain in this protein. We demonstrate that synthetic peptides corresponding to this domain of different retroviruses, including HIV, the baboon endogenous virus (BaEV), and different porcine endogenous retroviruses (PERVs), are immunosuppressive. We provide evidence that BaEV and different PERVs, including those able to grow in human cells, are immunosuppressive for lymphocytes of different species including human. This implies that xenotransplantation may result in a trans-species transmission of endogenous retroviruses derived from the donor animal. In analogy to HIV and SIV high-titer virus replication may cause an AIDS-like disease in the immunosuppressed human transplant recipient. Two additional points have to be considered: First, human anti-complement proteins produced by transgenic animals will also protect the virus and, second, the virus may be transmitted to other humans and thus increase its pathogenic potential.