TARGETING OF RETROVIRUSES TO SPECIFIC CELL TYPES

The long term goal of the studies described in this proposal is to
develop methods by which retroviruses and retroviral vectors may
be targeted to specific cell types. These investigations are of
medical significance because of the potential therapeutic value of
employing targeted retroviral vectors for the treatment of
genetically determined birth defects. Moreover, these studies
should yield detailed information as to the mechanisms by which
the Moloney murine leukemia virus (Mo-MuLV) envelope (env)
proteins become incorporated into viral particles, the
structure/function relationships of the Mo-MuLV env proteins, and
the putative association of the env proteins with the Mo-MuLV
core (gag) proteins. The model system described is ideal for the
elucidation of general mechanisms of viral assembly and of cell
surface and cytoplasmic protein interaction. The specific aims
are as follows: 1. We will undertake studies of mutant Mo-MuLV env proteins
(the gp70/p15E complex) with respect to their subcellular
localization, ability to be incorporated into viral particles, and
facilitation of viral entry into cells. 2. Non-retroviral "targeting" proteins, or fusions of such proteins
with the Mo-MuLV envelope proteins will be examined to
determine the factors which permit incorporation of heterologous
proteins into retroviral particles. 3. Mutations in Mo-MuLV gag genes which may affect the
incorporation of env proteins into virions will be generated and
analyzed. Gag gene sequences responsible for directing the
Pr65gag polyprotein to cell membranes and viral particles will be
identified by analysis of gag gene fusions to indicator genes.