Susceptibility of inbred strains of mice to murine AIDS (MAIDS) correlates with target cell expansion and high expression of defective MAIDS virus

Abstract

Murine AIDS (MAIDS) is readily induced by the Duplan strain of defective murine leukemia virus in susceptible C57BLJ6 mice. To identify mouse strains resistant to MAIDS, and to understand the genetic factors controlling susceptibility to the disease, we screened more than 20 inbred strains of mice for their susceptibility to MAIDS. For this study, mice of the Fv-1l'/ Fv-1b', or Fv-l/b genotype were inoculated with stocks of defective MAIDS virus pseudotyped with N-tropic, B-tropic, or NB-tropic helper murine leukemia virus, respectively. Strains could be classified as susceptible, resistant, or moderately resistant. None of the individual H-2 haplotypes examined appears to explain resistance to MAIDS by itself. However, a very good correlation between the susceptibility or resistance phenotype and the presence or absence of defective proviral DNA and RNA in the spleen of these animals was found. Since the presence of defective proviral DNA and RNA reflects the oligoclonal proliferation of the cells infected by the defective MAIDS virus, our results strongly suggest that this target cell expansion is genetically controlled and is necessary and perhaps even sufficient for the development of the disease.

Mutational analysis of the murine AIDS-defective viral genome reveals a high reversion rate in vivo and a requirement for an intact Pr60gag protein for efficient induction of disease

“…A very strong defective viral RNA band was detected in all mice injected with the control wild-type Du5H virus (Fig. 8A, lanes 16 to 20), confirming previous results (9,10). In contrast, this 4.2-kb RNA species was barely detectable or absent in all (5) samples from animals inoculated with mutant Du5H-B and Du5H-C viruses (Fig.…”

“…T-cell response to ConA. Concanavalin A (ConA) assays were performed with spleen cells, as previously described (10,26). Briefly, increasing concentrations of ConA (from 0 to 20 g/ml) were added in triplicate to wells of a Nunc culture plate previously seeded with 2 ϫ 10 5 splenocytes.…”

“…RNA extraction and hybridization. Total RNA was extracted by the method of Chomczynski and Sacchi (5), separated on 1% formaldehyde-agarose gels, transferred to nitrocellulose membranes, and hybridized with 32 P-labeled D30 probe, as previously described (9,10).…”

Impact of MHC Class I Gene on Resistance to Murine AIDS

“…Induction of MAIDS is dependent on infection by and spread of a defective vims, BM5def [3,4] or Du5H [5], that encodes an unusual gag polyprotein [3][4][5]. Strain differences in the ability to develop of MAIDS following infection with LP-BM5 MuLV are genetically determined, with major influences being exerted by genes both within and outside the MHC [6][7][8][9][10]. Analyses of strains bearing naturally occurring recombinants within H-2 revealed a prominent role for D end loci in resistance to MAIDS, an observation confirmed by the finding that otherwise susceptible H-2'' mice were rendered disease resistant following introduction and high level expression of H-2D^ as a transgene [8].…”

“…The resistance provided by the D*^ gene might Abbreviations: MuLV, murine leukaemia virus; MAIDS, murine AIDS; CTL, cytotoxic T lymphocyte; B6, C57BL/6 mice. be influenced, however, by background genes, since A lineage strains were thought to be more resistant than B6/B10 lineage mice in spite of bearing identical MHC genes [10]. There are also some genes which are apparently associated with the susceptibility to LP-BM5 MuLV infection but are highly influenced by background genes, for example, the xid gene in BlO-xW/x/rfmice [6,11] and H-2' genes in RIIIS mice [9].…”