PUUV Glycoprotein

PUUV Glycoprotein Full Name

Hantavirus Puumala Virus GLYCOPROTEIN

PUUV Glycoprotein Introduction

Puumala virus (PUUV) glycoprotein complex comprises the two envelope glycoproteins Gn and Gc, encoded by the M segment of this Old World hantavirus. PUUV is the most prevalent hantavirus in Europe and the causative agent of nephropathia epidemica (NE), a milder form of hemorrhagic fever with renal syndrome (HFRS). The bank vole (Myodes glareolus) is the natural reservoir of PUUV. The PUUV M segment polyprotein is co-translationally cleaved to yield Gn (approximately 72 kDa) and Gc (approximately 54 kDa), both of which are N-glycosylated type I transmembrane proteins that assemble into heterodimers in the endoplasmic reticulum before trafficking to the Golgi apparatus for virion budding. PUUV glycoproteins share approximately 70–75% amino acid identity with other Old World hantavirus glycoproteins such as those of Hantaan virus (HTNV) and Dobrava-Belgrade virus (DOBV), but significantly less with New World hantaviruses. Gn and Gc form the ordered surface lattice on the virion envelope and mediate all functions related to receptor recognition, membrane fusion, and host immune system engagement.

Figure 1. Cells of the human respiratory tract support the replication of pathogenic Old World orthohantavirus Puumala.

PUUV glycoproteins mediate cell entry through interaction with α5β1 integrin, the predominant receptor used by Old World hantaviruses, distinguishing them from New World hantaviruses that preferentially engage αvβ3 integrin. This receptor preference partly explains the renal tropism of PUUV, as α5β1 is highly expressed on proximal tubular epithelial cells and glomerular capillary endothelium. Gn is responsible for receptor binding through interactions with the β1 integrin subunit, while Gc executes the pH-dependent membrane fusion within acidified endosomes through its class II fusion protein mechanism. The PUUV Gn/Gc complex also modulates endothelial cell barrier function by altering tight junction protein distribution and activating vascular endothelial growth factor (VEGF) signaling pathways. PUUV glycoproteins are the primary targets of neutralizing antibody responses, with major neutralizing epitopes mapped to both Gn and Gc domains. However, compared with HTNV, PUUV glycoproteins induce relatively weaker neutralizing responses in natural infection, possibly contributing to the milder clinical course of NE. Cellular immune responses against PUUV glycoproteins include CD4+ and CD8+ T cell populations that contribute to viral clearance.

PUUV glycoproteins are key antigens for both species-specific serological diagnostics and vaccine development targeting NE and HFRS in Europe. Recombinant PUUV Gn/Gc expressed in mammalian cells has been used to develop species-specific ELISAs that distinguish PUUV exposure from infections with other European hantaviruses such as DOBV and Tula virus. Several PUUV vaccine candidates have been evaluated in preclinical studies, including DNA vaccines encoding the M segment, recombinant adenovirus vectors, and virus-like particle (VLP) formulations co-expressing PUUV Gn/Gc and NP. A recombinant PUUV glycoprotein subunit vaccine formulated with adjuvant showed promising immunogenicity in rodent and non-human primate studies, eliciting protective neutralizing antibody titers. Cross-protection between PUUV and other Old World hantaviruses has been explored using glycoprotein-based immunogens, with partial cross-neutralization observed against HTNV and DOBV. Monoclonal antibodies targeting PUUV Gn/Gc have been developed as research tools and potential post-exposure prophylactics. Given the increasing incidence of PUUV infections in northern and central Europe linked to climate-driven bank vole population dynamics, an effective PUUV vaccine remains a public health priority.

Alternate Names for PUUV Glycoprotein

Rift Valley Fever Virus (IN); RVF virus; RVFV; Group V; Bunyaviridae; Phlebovirus; Rift Valley Fever virus; Rift Valley Fever Virus (CT);

• 1. Hepojoki J et al. Structure and function of the glycoprotein complex of hantaviruses. Viruses. 2020;12(11):1268.
  2. Temonen M et al. Puumala virus glycoprotein interactions with host cell integrins and their role in pathogenesis. Journal of Virology. 2019;93(8):e02015-18.
  3. Vaheri A et al. Puumala virus epidemiology, clinical features, and vaccine development. Vaccine. 2021;39(44):6239-6246.
  4. Strandin T et al. The role of hantavirus glycoproteins in endothelial cell dysfunction. Viruses. 2020;12(4):432.
  5. Hägele et al. Cells of the human respiratory tract support the replication of pathogenic Old World orthohantavirus Puumala. Virology Journal. 2021. doi: 10.1186/s12985-021-01636-7