Tetraspanins in Viral Infections: a Fundamental Role in Viral Biology?

Abstract

4The tetraspanins are a broadly expressed superfamily of transmembrane glycoproteins with over 30 members found in humans and with homologues conserved through distantly related species, including insects, sponges, and fungi. Members of this family appear to form large integrated signaling complexes or tetraspanin-enriched microdomains (TEMs) by their association with a variety of transmembrane and intracellular signaling/cytoskeletal proteins (49). These interactions link tetraspanins to an array of physiological functions and, in consequence, to numerous endogenous pathologies, including cancer development and inherited disorders (Table 1).Tetraspanins are also known to have roles in the pathology of infectious diseases such as diphtheria, malaria, and numerous viral infections (Table 1). The literature currently indicates that specific tetraspanin family members are selectively associated with specific viruses and affect multiple stages of infectivity, from initial cellular attachment to syncytium formation and viral particle release. Thus, the relationship of tetraspanins with viruses appears to be particularly complex.Here, we will consider this data in the context of recent developments in tetraspanin biology, particularly in our understanding of the architecture and function of TEMs. With the benefit of recent insights into tetraspanin function in cell fusion events and intracellular trafficking, we discuss common features of tetraspanin/viral associations which indicate a fundamental role for TEMs in a number of viral infections. We will also consider the existing therapeutic strategies for human immunodeficiency virus (HIV), hepatitis C virus (HCV), and human T-cell lymphotropic virus type 1 (HTLV-1), focusing on the potential therapeutic value of targeting TEMs, using peptide reagents based on tetraspanin extracellular regions.

Normal muscle regeneration requires tight control of muscle cell fusion by tetraspanins CD9 and CD81

“…CD81 À / À mice are hypofertile and CD9 À / À ::CD81 À / À mice are completely infertile, suggesting a cooperative role of CD9 and CD81 in sperm/egg fusion 13 . However, both CD9 and CD81 negatively regulate HIV-induced cell fusion 14 and macrophage fusion 15 . Altogether, these studies indicate that CD9 and CD81 can act both as positive and negative regulators of cell-cell fusion processes.…”

Identification and characterization of the first reptilian CD9, and its expression analysis in response to bacterial infection

“…There is increasing evidence for the involvement of tetraspanins in infections by various microbes (especially by virus) [13]. Also, it has been reported that CD9 is up-regulated upon T cell activation [33].…”

“…In addition, in mammals, the tetraspanins have been known to have roles in the pathology of infectious diseases such as diphtheria, malaria and numerous viral infections (reviewed in Ref. [13]). In this study, a CD9 homologue in a reptile, Chinese soft-shelled turtle, has been cloned and identified for the first time.…”

Therapeutic and diagnostic applications of extracellular vesicles

“…GM3, sphingomyelin and cholesterol) and stimulate membrane fusion [51,111] as well as surface proteins that have likewise been linked to membrane fusion in cell-cell and viruscell interactions (e.g. CD9, CD81) [112,113] and finally (5) EVs seem to possess intrinsic cell and tissue targeting properties [114].…”