Recombinant gp41, the transmembrane glycoprotein of the human-immunodeficiency-virus (HIV) envelope, is an amino acceptor and donor substrate for transglutaminase in vitro. Gln51, Gln52, Gln66 and Lys77 residues were suggested as reactive sites, recognized by the enzyme, for possible cross-linking reactions with gp120, CD4 or other receptor(s) occurring on the surface of HIV-target cells. Soluble CD4, even though unable to function as an amino-acceptor transglutaminase substrate, becomes active in the presence of gp41, negatively influencing the enzyme-catalyzed incorporation of the polyamine spermidine into the transmembrane protein. These results suggest a possible role for transglutaminase in virus entry into host cells, via receptor-mediated endocytosis, and/or in HIV-induced CD4+ T-cell depletion via apoptosis.