ANALYSIS OF HOST-RANGE RESTRICTION DETERMINANTS IN THE RABBIT MODEL -COMPARISON OF HOMOLOGOUS AND HETEROLOGOUS ROTAVIRUS INFECTIONS

The main Limitation of both the rabbit and mouse models of rotavirus i nfection is that human rotavirus (HRV) strains do not replicate effici ently in either animal. The identification of individual genes necessa ry for conferring replication competence in a heterologous host is imp ortant to an understanding of the host range restriction of rotavirus infections. We recently reported the identification of the P type of t he spike protein VP4 of four lapine rotavirus strains as being P[14]. To determine whether VP4 is involved in host range restriction in rabb its, we evaluated infection in rotavirus antibody-free rabbits inocula ted orally with two P[14] HRVs, PA169 (G6) and HAL1166 (GS), and with several other HRV strains and animal rotavirus strains of different P and G types. We also evaluated whether the parental rhesus rotavirus ( RRV) (P5B[3], G3) and the derived RRV-HRV reassortant candidate vaccin e strains RRV x D (G1), RRV x DS-1 (G2), and RRV x ST3 (G4) would prod uctively infect rabbits. Based on virus shedding, limited replication was observed with the P[14] HRV strains and with the SA11 CI3 (P[2], G 3) and SA11 4F (P6[1], G3) animal rotavirus strains, compared to the h omologous ALA strain (P[14], G3). However, even limited infection prov ided complete protection from rotavirus infection when rabbits were ch allenged orally 28 days postinoculation (DPI) with 10(3) 50% infective doses of ALA rabbit rotavirus. Other HRVs did not productively infect rabbits and provided no significant protection from challenge, in spi te of occasional seroconversion. Simian RRV replicated as efficiently as lapine ALA rotavirus in rabbits and provided complete protection fr om ALA challenge. Live attenuated RRV reassortant vaccine strains resu lted in no, limited, or productive infection of rabbits, but all rabbi ts were completely protected from heterotypic ALA challenge. The alter ed replication efficiency of the reassortants in rabbits suggests a ro le for VP7 in host range restriction. Also, our results suggest that V P4 may be involved in, but is not exclusively responsible for, host ra nge restriction in the rabbit model. The replication efficiency of rot avirus in rabbits also is not controlled by the product of gene 5 (NSP 1) alone, since a reassortant rotavirus with ALA gene 5 and all other genes from SA11 was more severely replication restricted than either p arental rotavirus strain.