and the VA Palo Alto Health Care System, Palo Alto, California, USA Homologous rotaviruses (RV) are, in general, more virulent and replicate more efficiently than heterologous RV in the intestine of the homologous host. The genetic basis for RV host range restriction is not fully understood and is likely to be multigenic. In previous studies, RV genes encoding VP3, VP4, VP7, nonstructural protein 1 (NSP1), and NSP4 have all been implicated in strain-and host species-specific infection. These studies used different RV strains, variable measurements of host range, and different animal hosts, and no clear consensus on the host range restriction determinants emerged. We used a murine model to demonstrate that enteric replication of murine RV EW is 1,000-to 10,000-fold greater than that of a simian rotavirus (RRV) in suckling mice. Intestinal replication of a series of EW Ű RRV reassortants was used to identify several RV genes that influenced RV replication in the intestine. The role of VP4 (encoded by gene 4) in enteric infection was strain specific. RRV VP4 reduced murine RV infectivity only slightly; however, a reassortant expressing VP4 from a bovine RV strain (UK) severely restricted intestinal replication in the suckling mice. The homologous murine EW NSP1 (encoded by gene 5) was necessary but not sufficient for promoting efficient enteric growth. Efficient enteric replication required a constellation of murine genes encoding VP3, NSP2, and NSP3 along with NSP1.
Group A rotaviruses (RVs) are segmented double-stranded RNA viruses that replicate primarily in mature epithelial cells on the tips of the small intestinal villi (1). Rotavirus infection is ubiquitous among mammals; however, viral strains isolated from one host species tend to have diminished replication capacity and virulence in heterologous species. This host range restriction was the basis for two modified "Jennerian" RV vaccines, RotaShield and RotaTeq; animal rotaviruses that are naturally restricted for replication and virulence in humans were used as genetic backbones to produce these attenuated, live viral human vaccines. In the pentavalent RV vaccine Rotateq, for example, human rotavirus genes encoding VP7 of serotypes G 1, 2, 3, 4, and VP4 of serotype P1A (P[8]) were incorporated into bovine RV strain WC3. It was thought that the multivalent nature of this vaccine would induce neutralizing antibodies against the most common human RV serotypes but that it would be attenuated in susceptible infants because of host range restriction elements in its bovine (heterologous) RV backbone (2).Direct experimental evidence for host range restriction has been best demonstrated in the murine system, where all known heterologous RV strains replicate orders of magnitude less efficiently in suckling mice than do homologous murine strains (3, 4). On the other hand, experimental studies in gnotobiotic piglets have been interpreted to indicate that some human RV strains can be adapted to replicate very efficiently in piglets, although direct comparison to wild-t...