HIV-1 induces like many other retroviruses a severe immunodeficiency in the infected host. Inactivated retroviruses, their transmembrane envelope (TM) proteins and synthetic peptides corresponding to a highly conserved domain in their TM protein, the so-called immunosuppressive (Isu) domain, have been shown to induce inhibition of lymphocyte proliferation, as well as a modulation of cytokine release and expression of cellular genes. Therefore it was suggested that the Isu domain of the retroviral TM proteins is involved in immunopathogenesis. Point mutations in the Isu domain have been shown to abrogate the biological activity. To study this in more detail, a recombinant gp41 was produced in a human cell line. The protein was purified and characterised by several methods showing glycosylation of the protein and assembling into trimers. Binding studies by ELISA and surface plasmon resonance using conformation-specific monoclonal antibodies imply a six-helix bundle conformation. Purified gp41 bound to monocytes and to a lesser extend to lymphocytes. In parallel, homopolymers of peptides corresponding to the Isu domain were also found to bind specifically to monocytes and B cells. Gp41 triggered the production of specific cytokines when incubated with human peripheral blood mononuclear cells. Among them IL-10. Furthermore, gp41 expressed on murine target cells inhibited the antigen-specific response of murine CD8+ T cells by impairing their IFNγ production. The expression of CD25 was also impaired. These data confirm previous findings on the interspecies-reactivity of the Isu domain and suggests highly conserved binding proteins. In summary, these data provide additional evidence that gp41 might be directly involved in HIV-1 immunopathogenesis.