Identification, using synthetic peptides, of the minimum amino acid sequence from the retroviral transmembrane protein p15E required for inhibition of lymphoproliferation and its similarity to gp21 of human T-lymphotropic virus types I and II

Abstract

Synthetic peptides containing portions of a highly conserved region of retroviral transmembrane proteins of human and animal retroviruses were tested for their ability to inhibit lymphoproliferation to determine the minimum amino acid sequence required. The previously reported immunosuppression mediated by the peptide CKS-17 was confirmed and further localized to a sequence of eight residues essentially identical to the sequence present in the transmembrane protein gp2l of human T-lymphotropic virus types I and II (HTLV-I and-II). To substantiate the physiological relevance of the inhibition of lymphoproliferation observed with the synthetic peptides and to relate this activity to the intact protein, we purified the Rauscher murine leukemia virus transmembrane protein pl5E by immunoaffinity chromatography and report that this purified component presented in the form of protein micelles inhibited the interleukin-2-dependent proliferation of the murine T-cell line CTLL-2 in a dose-dependent manner, with a half-maximal inhibitory dose (ID50) of-16 nM. In comparison, the ID50 concentration of a recombinant form of pl5E required to inhibit lymphoproliferation was-2.2 ,uM. The results reported here support the hypothesis that the transmembrane protein gp2l of HTLV-I and-II participates in the mechanism of immunosuppression previously reported for the transmembrane proteins of feline leukemia virus and other animal retroviruses. Thus, the transmembrane protein of HTLV-I, the etiological agent of adult T-cell leukemia-lymphoma, may be partially responsible for the immunocompromised clinical course of this disease that results in fatal opportunistic infections in a majority of cases.

Sensitivity and specificity of a recombinant transmembrane glycoprotein (rgp21)-spiked western immunoblot for serological confirmation of human T-cell lymphotropic virus type I and type II infections

“…While rgp2l-spiked WB is highly sensitive and may eliminate the need for RIPA for serologic confirmation of HTLV-I or HTLV-II infection, it is extremely important to determine the specificity of this assay. In particular, the transmembrane proteins of the majority of retroviruses are highly conserved (7,16). In this study, specimens from nearly 6% of HTLVind individuals from the United States (21 of 379) reacted with rgp2l and failed to react with native gp46 and/or gp6l/68.…”

The Potential Roles of Endogenous Retroviruses in Autoimmunity

“…Likewise, cAMP and cGMP levels were demonstrated to be increased in a T-cell line and normal PBMCs after infection with HIV (Nokta & Pollard 1991). Furthermore, peptide amino acids 581-597 in the transmembrane gp41 of HIV, which also has sequence similarity to pl5E, was shown to inhibit lymphoproliferative responses to stimulation by anti-CD3 and IL-2 (Cianciolo et al 1988, Ruegg et al 1989a. Therefore, pl5E or similar peptides may be involved in dysregulation of immune responses observed with retroviral infection, e.g.…”

Novel Mechanistic Insights into Viral Modulation of Immune Receptor Signaling

“…Intriguingly, analysis of other unrelated viruses has yielded similar correlations in primary structure and function. Earlier studies have reported an inhibitory effect on lymphocyte proliferation by CKS-17 peptide, a synthetic 17mer peptide with sequence corresponding to a highly conserved region of TM proteins of human and animal retroviruses, including the TM protein gp21 of human T lymphotropic virus type 1 (HTLV-1) [34][35][36]. Interestingly, peptides corresponding to regions of HIV TM protein gp41 homologous to the highly conserved and immunosuppressive sequence contained within the TM proteins p15E and gp21 of animal and human retroviruses, respectively, also have been reported to inhibit lymphoproliferation , shown as a simplified axial view) and prevents formation of signaling oligomers upon antigen but not antibody stimulation, thus inhibiting antigen-mediated but not anti-CD3-mediated TCR triggering and cell activation (D).…”

“…Thus, helical wheel projections are used for illustrative purposes only; the suggested mode of action does not depend on a particular secondary structure of the sequences. [35,36]. Recently, filoviral 17-mer peptides corresponding to a 17-amino acid domain in filoviral glycoproteins that resembles an immunosuppressive motif in retroviral envelope proteins have been demonstrated to inhibit TCR-mediated cell activation [37].…”