A once-exotic group of rodent-borne viruses, known to cause an acute interstitial nephropathy of varying severity called hemorrhagic fever with renal syndrome (HFRS), gained notoriety in the spring of 1993, when a terrifying outbreak of an acute, frequently fatal respiratory illness, now known as hantavirus pulmonary syndrome (HPS), occurring in the Four Corners region of the southwestern United States, was etiologically linked to a newly identified hantavirus harbored by the deer mouse (Peromyscus maniculatus). The newly identified virus, previously designated Four Corners virus and Muerto Canyon virus and now known as Sin Nombre virus, and other viruses belonging to the Hantavirus genus of the Bunyaviridae family possess a negative-sense, single-stranded RNA genome, comprised of three segments, designated large (L), medium (M) and small (S), which encode an RNA-dependent RNA polymerase, the G1 and G2 envelope glycoproteins, and a nucleocapsid protein, respectively. Each of the genetically and biologically distinct hantaviruses is harbored by a specific rodent or insectivore host. The cellular entry of hantaviruses which cause HFRS and HPS is mediated by b3 integrins.

We have studied the integrin usage requirements for cellular entry of three additional hantaviruses, which are not known to cause human disease and which were isolated from disparate geographic settings: Prospect Hill (PH) virus, isolated from the meadow vole, Microtus pennslyvanicus, captured in Frederick, Maryland; two Tula virus (TUL) isolates from the European common vole, Microtus arvalis, captured in Czechoslovakia and Poland; and Thottapalayam (TPM) virus, isolated from the musk shrew, Suncus murinus, captured in Tamil Nadu, Vellore, India. Infection of Vero E6 cells by TUL, PH and TPM viruses was inhibited by pretreating cells with specific sera to a5 (65-70%), b1 (80-90%), a5b1 (80-90%), or the integrin ligand, fibronectin (60-70%). Although RGD tripeptides are required for many integrin-ligand interactions, hantavirus proteins lack RGD motifs and similar to pathogenic hantaviruses the interaction of nonpathogenic hantaviruses with cellular integrins is not blocked by GRGDP peptides and is RGD independent. These viruses are antigenically and genetically distinct, isolated from unique animal hosts in disparate parts of the world, yet are blocked by identical integrin-specific sera and ligands. Our findings indicate that b3 and b1 integrins distinguish the entry of pathogenic from nonpathogenic hantaviruses and correlate b1 integrin usage with a nonpathogenic hantavirus phenotype.