The decameric repeat (DR) of PSGL-1 functions as a basic antiviral unit in restricting HIV-1 infectivity

PSGL-1 is a dimeric, mucin-like glycoprotein known to act as an HIV-1 restriction factor. It functions by incorporating itself into budding virions, where it physically blocks the virus from attaching to new target cells. The protein’s structure is dominated by a large extracellular mucin-like domain composed of 14 to 16 tandem decameric repeats (DRs). While these repeats are known to elongate the protein backbone, their specific contribution to antiviral restriction has remained poorly understood.

Researchers employed a systematic mutagenesis strategy, creating a panel of PSGL-1 variants with varying numbers of DRs—ranging from full-length molecules to single-unit mutants. They assessed these mutants using virion incorporation, viral attachment, and infectivity assays to quantify the impact of DR length and sequence. Additionally, the study used all-atom replica exchange molecular dynamics (REST) simulations to model the conformational behavior of individual DRs and elucidate the structural properties, such as backbone dihedral angles and atom density distributions, that govern antiviral potency. Finally, they tested if the DR domain’s antiviral function was portable by inserting it into a non-antiviral protein, CD2.

The study establishes that the DR domain is essential for PSGL-1-mediated restriction. Deleting all DRs abolishes the protein's ability to hinder virion attachment, even if the truncated protein is still successfully incorporated into the virus. Crucially, even a single DR is sufficient to confer a basic, measurable level of antiviral activity, demonstrating that the DR serves as a modular, fundamental unit of inhibition. The researchers found that antiviral potency correlates with the number of DRs, suggesting a cumulative mechanism. Molecular modeling indicates that this potency is tied to the structural elongation of the DR backbone; more rigid, extended conformations are associated with higher antiviral effectiveness. Furthermore, the DR domain’s function is transferable, as inserting it into the extracellular domain of CD2 partially conferred anti-HIV properties to the hybrid molecule.