DI influenza viruses arise readily and their study has a long history extending back over 60 years
[5], [11], [12] and [13]. DI RNAs can potentially arise from all viral segments, but are most commonly derived from segments 1–3. All influenza DI RNAs formed from their cognate RNA and contain a large central deletion of approximately 80%, but retain the terminal sequences which selleckchem control replication and packaging. It is hypothesized that an infectious particle packages one of each of full-length segments 1–8, while the DI virus particle packages a DI RNA in place of its cognate full-length RNA, plus the other 7 full length RNAs. Most DI influenza virus preparations contain many different DI RNA sequences, but it is not known if a single DI particle can contain more than one DI RNA, or if there are other DI particles in the preparation that contain a DI RNA derived from a different segment. The position and extent of the central deletion in the DI RNA is highly variable so that DI RNAs originating from one genomic segment can have many different sequences. For all these reasons it has been difficult to determine the relationship between a DI RNA sequence and the biological properties of the DI
virus [14]. We recently solved this problem by using molecularly or biologically cloned viruses that contain one major species of DI RNA [14], [15], [16], [17] and [18], and subsequently characterized one DI virus, containing RNA 244, that strongly protects mice from clinical disease caused by various influenza selleck kinase inhibitor A virus subtypes [18]. However, it is not understood how influenza DI virus mediates such protection in vivo. In principle, DI viruses could act in vivo by interfering with the production of homologous virus (as described above), by stimulating adaptive immune responses, by stimulating innate immune responses, or
by means as yet unknown. More than one of these mechanisms may operate at any one time. We have shown previously that various aspects of the humoral and T cell-mediated arms of murine adaptive immunity interact with infectious virus in the presence of non-cloned DI whatever influenza A virus. The data showed that the responses to infection were modified in several unusual ways by the presence of active DI virus (see Section 4) [19], [20], [21], [22], [23], [24] and [25]. Here we investigate how severe combined immunodeficient (SCID) mice that completely lack adaptive immunity but retain NK cell activity respond to a mixture of infectious virus and in conjunction with treatment with cloned DI virus that confers protection from disease in immune-competent animals. SCID mice have been used extensively for investigating the role of the immune system in recovery from influenza virus infections [26], [27], [28], [29], [30] and [31]. Analysis of the mechanism(s) by which DI viruses prevent disease in treated animals is not fully understood.