Mutants of murine leukemia viruses and retroviral replication

Abstract

The analysis of retroviral mutants has played a critical role in the development of our understanding of the complex viral life cycle. The most fundamental result of that analysis has been the definition of the replication functions encoded by the viruses. From a biochemical examination of a particular step in the life cycle it is difficult to determine, for example, whether that step is catalyzed by a viral or a host enzyme; but the isolation of a viral mutant defective in that step can firmly establish that a viral function is involved. In this way many facts about the viruses have been established. We know that reverse transcriptase is encoded by the virus; that RNAase H and DNA polymerase activities reside on the same gene product; that processing of many precursor proteins is mediated by a viral proteinase; and that establishment of the integrated provirus requires a viral protein. The list of functions mediated by viral enzymes has largely been defined by the mutants isolated and studied in various laboratories. The second significant result of the studies of viral mutants has been the assignation of the replication functions to particular viral genes, and then more specifically to particular domains of these genes. Mutants and viral variants have been essential in the determination, for example, that the gag protein is the critical gene product for the assembly of a virion particle; that the env protein is the determinant of species specificity of infection; or that the LTR is a major determinant of tissue tropism and leukemogenicity. The subdivisions of functions within a given gene have similarly hinged on mutants. Genetic mapping was needed to establish that P30 is the most important region for assembly; that the proteinase and integrase functions reside, respectively, in the 5' and 3' portions of the pol gene; and that the glycosylated gag protein is dispensable for replication. A third important area of knowledge has depended heavily on viral mutants: the determination of host functions and proteins that interact with viral proteins. Variant viruses with altered or restricted host ranges serve to define differences between pairs of different host cells, and the mapping of the viral mutations serves to define the viral protein important in that interaction with the host. These studies are only in their infancy, but it is clear that substantial efforts will be made to further analyze these host functions.(ABSTRACT TRUNCATED AT 400 WORDS)