Targeting MIRRs: suggested immunomodulatory strategies used by viruses to enter target cells, survive and replicate. Transmembrane interactions between MIRR recognition and signaling subunits are shown by black arrows. Extracellular ligand-binding domains are shown by red. Immunoreceptor tyrosine-based activation motifs (ITAMs) are denoted by green. Circular arrow indicates viral agent-induced receptor clustering. Curved lines depict intrinsic disorder of the cytoplasmic domains of MIRR signaling subunits.

SCHOOL insights into the mode of action of immunomodulatory viral sequences targeting T-cell receptor. (A) Structural architecture of T-cell receptor is organized by three major assembly transmembrane forces, each involving one basic and two acidic amino acid residues highlighted by blue and red, respectively (shown as a simplified axial view). (B) The experimentally observed striking similarities in characteristics and immunomodulatory activities of TCRα TMP and HIV-1 gp41 FP [Amon MA, Ali M, Bender V, Chan YN, Toth I, Manolios N. Biochim Biophys Acta 2006; 1763:879–88; Enk AH, Knop J. Int Arch Allergy Immunol 2000; 123:275–81; Wang XM, Djordjevic JT, Bender V, Manolios N. Cell Immunol 2002; 215:12–9; Wang XM, Djordjevic JT, Kurosaka N, Schibeci S, Lee L, Williamson P, et al. Clin Immunol 2002; 105:199–207; Quintana FJ, Gerber D, Kent SC, Cohen IR , Shai Y. J Clin Invest 2005; 115:2149–58]. (C) Within the SCHOOL model, viral agents (V) compete with the TCRα chain for binding to the CD3δε and ζ signaling subunits and thus disrupt the transmembrane interactions between the ligand-binding TCRα chain and these signaling chains. This results in disconnection and pre-dissociation of the affected signaling subunits from the remaining receptor complex and prevents formation of signaling oligomers upon multivalent antigen stimulation, thus inhibiting T-cell activation. In contrast, stimulation of this “pre-dissociated” TCR with cross-linking antibodies to signaling subunit(s) still leads to receptor triggering and cell activation. FP, fusion peptide; HIV, human immunodeficiency virus; ND, not determined; PMA, phorbol 12-myristate 13-acetate; TCRα TMP, T-cell receptor alpha chain transmembrane peptide; V, viral agent.

Primary sequence analysis of proven and predicted immunomodulatory sequences of viral fusion protein regions and other domains. Similarities in charge distribution pattern with two essential positively charged residues (shown in bold blue) spaced apart by 3–4 or 7–8 amino acids suggest a similarity of mechanisms used by diverse viruses in their pathogenesis to modulate the host immune response. Note: Although the three-dimensional structures of the analyzed sequences within the cell membrane are not known, it might be assumed that these sequences may adopt a helical conformation upon membrane binding. 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. As an ideal alpha helix consists of 3.6 residues per complete turn, the angle between two residues is chosen to be 100 degrees and thus there exists a periodicity after five turns and 18 residues. For this reason, the regions shown are restricted to 18 residues. CKS-17, a synthetic retroviral envelope heptadecapeptide; FP, fusion peptide; Fr-MLV, Friend murine leukemia virus; gp, glycoprotein; HHV-6 U24, human herpesvirus 6 U24 protein; HIV, human immunodeficiency virus; HTLV-1, human T lymphotropic virus type 1; HVA, herpesvirus ateles; HVS, herpesvirus saimiri; LASV, Lassa virus; LCMV, lymphocytic choriomeningitis virus; MARV, Marburg virus; MOPV, Mopeia virus; SARS-CoV, severe acute respiratory syndrome coronavirus; SEBOV, Sudan Ebola virus; TACV, Tacaribe virus; Tip, tyrosine kinase-interacting protein; Tio, two-in-one protein; TCRα, T-cell receptor alpha chain; TMD, transmembrane domain; TMP, transmembrane peptide; ZEBOV, Zaire Ebola virus.