GENETIC STRUCTURE OF MURINE RETROVIRUSES

这个实验室的主要研究重点是遗传变异

The major focus of research in this laboratory is the genetic variation of retroviruses, including variation as a result of point mutation as well as variation due to recombination of retroviral genes. Genetic variation occurs in all retrovirus infections, including avian, murine and human retroviruses such as HIV. Most of our current studies focus on the polymorphism of recombinant host range retrovirus variants and the characterization of endogenous retroviral sequences which are involved in the generation of the variants. Inoculation of many murine retroviruses in mice results in the generation of host range variants by recombination of the inoculated virus with endogenous retroviral genes. We have identified two major antigenic subgroups of these variants distinguished by their reactivity with two monoclonal antibodies (mAbs) and have defined the position of a single amino-acid residue whose identity determines reactivity to the antibodies. Our results indicate that the two subgroups are the result of recombination of inoculated virus with two distinct families of endogenous retroviral sequences. Furthermore, we have found that inoculation of different retroviruses results in the generation of strikingly different proportions of the variant subgroups suggesting that different inoculated retroviruses preferentially recombine with different populations of endogenous retroviral genes. We are currently comparing the endogenously-derived gene sequences of variant viruses with each other and with retrovirus gene sequences found in uninfected mice. These studies should precisely identify which endogenous sequences participate in recombination to generate the host range variants. A second aspect of our studies is the mutation rate of retroviruses. In previous studies we have directly determined the mutation rate of a murine retrovirus and found that most progeny retroviruses do not sustain any point mutations during a single cycle in a fibroblastic cell line. We wish to extend these studies to determine if mutation rates are accelerated in different cell types, such as macrophages, and examine conditions which may alter mutation rates. Direct determinations of mutation rates are quite labor intensive and would limit progress in these studies. We are developing an alternative approach which exploits an antigenic conversion we have been able to effect by a single point mutation.