Humoral Immunity to Hantavirus Infection

Abstract

Hantaviruses are zoonotic pathogens found in parts of Europe, Asia, South America, and North America, which can cause renal and respiratory failure with fatality rates up to 40%. There are currently no FDA-approved vaccines or therapeutics for hantavirus-related diseases; however, it is evident that a robust neutralizing antibody response is critical for protection from severe disease. Although virologists first described this family of viruses in the 1950s, there is limited information on the neutralizing epitopes that exist on the hantavirus antigenic glycoproteins, Gn and Gc, and sites important for the design of effective therapeutics and vaccines. We provide a thorough summary of the hantavirus field from an immunological perspective. In particular, we discuss our current structural knowledge of antigenic proteins Gn and Gc, identification of B cell neutralizing epitopes, previously isolated monoclonal antibodies and their cross-reactivity between different hantavirus strains, and current developments toward vaccines and therapeutics. We conclude with some outstanding questions in the field and emphasize the need for additional studies of the human antibody response to hantavirus infection.IMPORTANCE Hantaviruses are pathogens that sometimes pass from animals to humans, and they are found in parts of Europe, Asia, and North and South America. When human infection occurs, these viruses can cause kidney or lung failure, and as many as 40% of infected people die. Currently, there are no vaccines or therapeutics for hantavirus-related diseases available. A first step in developing prevention measures is determining what type of immune response is protective. Increasingly it has become clear that the induction of a type of response called a neutralizing antibody response is critical for protection from severe disease. Although virologists first described this family of viruses in the 1950s, there is limited information on what features on the surface of hantaviruses are recognized by the immune system. Here, we review the current state of knowledge of this information, which is critical for the design of effective therapeutics and vaccines.

Keywords: B cell responses; antibody function; bunyavirus; hantavirus; neutralizing antibodies.

FIG 1

Previously identified antigenic sites on hantavirus glycoprotein Gn or Gc. (a and b) Neutralizing MAbs and epitopes for serum antibody recognition identified by peptide scanning and generation of escape mutant viruses are mapped on the crystal structure of Puumala virus Gn protein (PDB: 5FXU) in the tetrameric form on the surface of the virion. Gn is shown as a tetramer from the top view (a) or dimer from the side view (b). (c) Epitopes and escape mutations also are mapped to the linear genome of Gn. The signal peptide (SP) or transmembrane domain (TM) is highlighted in yellow or gray, respectively. (d and e) Previously identified neutralizing MAb and serological epitopes identified by peptide scanning and generation of escape mutant viruses are mapped on the crystal structure of Puumala virus Gc in the postfusion form of trimer (PDB: 5J9H). Gc is shown as a trimer (d) or protomer (e) to demonstrate epitopes that are inaccessible in the trimer. (f) Epitopes and escape mutations also are mapped to the linear genome of Gc. Domains I, II, and III are indicated in red, yellow, or blue, respectively, and the fusion loop is indicated in orange. Spheres indicating epitopes are color coded as follows: green, PUUV MAbs (5A2, 1C9, 4G2); purple, HTNV MAbs (M7, Y1, Y5, Y7, Y22); orange, sera from convalescent Sin Nombre patients; teal, sera from convalescent Puumala patients; pink, sera from convalescent ANDV patients. Escape mutations are indicated by the blue (anti-HTNV MAbs) or orange (anti-ANDV MAbs) bars.