Sep 17, 1998 - New York 1 and Sin Nombre Viruses Are Serotypically Distinct .... Virus-infected Vero E6 cells (NY-1, PH, PUU, or SEO) were bound to.
New York 1 and Sin Nombre Viruses Are Serotypically Distinct Viruses Associated with Hantavirus Pulmonary Syndrome Irina Gavrilovskaya, Rachel LaMonica, Mary-Ellen Fay, Brian Hjelle, Connie Schmaljohn, Robert Shaw and Erich R. Mackow J. Clin. Microbiol. 1999, 37(1):122.
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JOURNAL OF CLINICAL MICROBIOLOGY, Jan. 1999, p. 122–126 0095-1137/99/$04.0010 Copyright © 1999, American Society for Microbiology. All Rights Reserved.
Vol. 37, No. 1
New York 1 and Sin Nombre Viruses Are Serotypically Distinct Viruses Associated with Hantavirus Pulmonary Syndrome IRINA GAVRILOVSKAYA,1 RACHEL LAMONICA,1 MARY-ELLEN FAY,1 BRIAN HJELLE,2 CONNIE SCHMALJOHN,3 ROBERT SHAW,1,4 AND ERICH R. MACKOW1,4,5* The Department of Medicine1 and the Department of Molecular Genetics and Microbiology,5 Stony Brook University, Stony Brook, New York 11794, Department of Pathology, University of New Mexico, Albuquerque, New Mexico,2 The Northport VA Medical Center, Northport, New York 11768,4 and USAMRIID, Fort Detrick, Maryland3 Received 24 July 1998/Returned for modification 17 September 1998/Accepted 30 September 1998
Bayou virus (BAY) has also been associated with an HPS case in Louisiana (host, Oryzomys palustris), and El Moro Canyon virus (host, Reithrodontomys megalotis) exhibits similarity to HPS viruses but has yet to be associated with HPS (19, 26, 34, 48). The New York 1 hantavirus (NY-1) is similarly derived from an isolated geographic location, an island off the coast of New York (47). NY-1 is also associated with HPS, and we isolated NY-1 from a unique host species, the white-footed mouse Peromyscus leucopus (47). NY-1 and BCC surface glycoproteins are also highly divergent. However, NY-1 and SN are more closely related and share 93 and 97% amino acid identities in their G1 and G2 proteins, respectively (22, 35). In this study, we addressed the question of whether the 3 to 7% difference between NY-1 and SN glycoproteins specifies unique or common serotypic determinants. Reciprocal focus reduction neutralization (FRN) assays were performed on NY-1 and SN in order to determine their antigenic relationship. We report that serum neutralizing antibody titers to heterologous hantaviruses are 4- to 32-fold lower than those from animal or human sera to homologous hantaviruses. As a result, NY-1 and SN elicit unique neutralizing antibody responses and define discrete hantavirus serotypes. These findings indicate that 3 to 7% differences in hantavirus glycoproteins can confer serotypic differences between hantaviruses and further suggest that additional HPS-associated serotypes are likely to be identified in the Americas.
Hantaviruses are enveloped negative-stranded RNA viruses with a tripartite genome and comprise a distinct genus within the Bunyaviridae family (42). Hantaviruses are present worldwide and cause two human diseases: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) (41, 51). Each hantavirus is carried primarily by a specific small mammal host which is persistently infected (4, 5, 14, 19, 22, 27, 41). Hantaviruses are transmitted to humans through the inhalation of aerosolized excreta (29, 41). In the Americas, hantaviruses are the cause of HPS, an acute respiratory distress syndrome with a 45% mortality rate. HPS was first recognized in patients in the southwestern United States in 1993 and has subsequently been identified in 28 states and Canada (18, 36). Recently identified HPS cases in South America indicate that HPS-associated hantaviruses are widely dispersed and that some HPS-associated hantaviruses may be transmitted from person to person (11, 13, 25). Two integral membrane surface glycoproteins, G1 and G2, are present on the surface of hantaviruses (44, 50). Antibodies to G1 and G2 neutralize the virus, distinguish viral serotypes, and protect animals from hantavirus infection (1, 2, 6, 7, 9, 31). At present 11 distinct serotypes of hantavirus have been established: Hantaan (HTN), Puumala (PUU), Seoul (SEO), Dobrava, Khabarovsk, Thailand, Thottapalayam, Tula, Prospect Hill (PH), Sin Nombre (SN), and Black Creek Canal (BCC) (3–5, 8, 10, 23, 27, 28, 39, 40, 49). Thus far, HPS-associated viruses are represented by two serotypes, SN and BCC, with highly divergent G1 and G2 glycoproteins (38). SN is the prototype HPS-associated strain derived from the deer mouse, Peromyscus maniculatus, in the southwestern United States (10). In contrast, BCC was isolated from the Florida cotton rat, Sigmodon hispidus, and as a result BCC and SN are from discrete geographic locations and host species (6, 38, 39).
MATERIALS AND METHODS Cells, media, and viruses. Vero E6 cells were grown in Dulbecco’s Modified Eagle’s Medium (DMEM) containing 10% fetal calf serum (FCS, 56°C heat inactivated), penicillin (100 mg/ml), streptomycin sulfate (100 mg/ml), and amphotericin B (5 mg/ml). SN (CC107) (40), NY-1 (47), and PH (PH-1) (30) were grown on Vero E6 cells (ATCC CRL 1586) (12, 40, 43) in a biosafety level 3 facility. SN, PH, and NY-1 were adsorbed onto Vero E6 cell monolayers for 1 h, washed, and grown in maintenance medium (DMEM–2% FCS) (12, 40, 43). Maximal titers of NY-1, SN, and PH were between 5 3 106 and 1 3 107 focus forming units (FFU)/ml. Sera. Hyperimmune hamster reference sera to HTN, PUU, SEO, and PH were kindly provided by Ho Wang Lee at the World Health Organization Re-
* Corresponding author. Mailing address: Department of Medicine/ GI, Stony Brook University, HSC T17, Rm. 60, Stony Brook, N.Y. 11794. Phone: 516-444-2120. Fax: 516-444-8886. E-mail: EMackow @mail.som.sunysb.edu. 122
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New York 1 virus (NY-1) and Sin Nombre virus (SN) are associated with hantavirus pulmonary syndrome (HPS). NY-1 and SN are derived from unique mammalian hosts and geographic locations but have similar G1 and G2 surface proteins (93 and 97% identical, respectively). Focus reduction neutralization assays were used to define the serotypic relationship between NY-1 and SN. Sera from NY-1-positive Peromyscus leucopus neutralized NY-1 and SN at titers of >1/3,200 and
