Administration of retrovirally resistant cells to HIV infected humans is under active study. Using a murine model of acquired immunodeficiency induced by retroviruses, we explored the safety and efficacy of retrovirally resistant cells in a susceptible host animal. Two different strains of allophenic mice were constructed, in which one parent strain was susceptible and the other resistant to murine retroviruses. Importantly, the mechanism of retroviral resistance in the two resistant strain partners differed. Lymphoid chimerism of individual animals was assessed by flow cytometric techniques and the animals subsequently inoculated with the retroviral mix. The animals were assessed for time to lymphadenopathy, time to death, changes in flow cytometric parameters, and for recovery of retroviral species. Despite differences in mechanism of retroviral resistance, the presence of substantial, but less than predominant numbers of resistant cells afforded no protection against disease, with animals developing lymphadenopathy and dying in the same time frame or more rapidly than fully susceptible control mice and with comparable recovery of retroviral species. However, in multiple animals in which the predominant lymphoid population was of the resistant genotype, the animals failed to develop disease, and there was a marked reduction in level of retrovirus. Importantly, the fate of susceptible cells differed depending on the mechanism of disease resistance, with a marked reduction in the susceptible lymphoid cell compartment in one combination but no change in the other. Thus, it is apparent that there is a critical balance between susceptible and resistant lymphoid cells that determines whether the animals succumb to disease, or achieve long term resistance, and that the mechanism of resistance may determine the fate of the susceptible cell population. This model also addresses issues pertaining to changes in tropism of the infective retrovirus and of endogenous retroviruses, present in the genome of donor cells. Additional studies have been planned to identify the critical resistant cellular populations responsible for conferring protection against disease, for testing their safety when infused into retrovirally infected animals, and for assessing changes in viral tropism. Sechler, JMG, Lawler, A., Hartley, JW, Morse, HC,III, and Rosenberg, AS. Induction of MAIDS in Allophenic Mice Generated from Strains Susceptible and Resistant to Disease. Manuscript in Preparation.
