THE ENVELOPE GENE PRODUCTS OF MURINE LEUKEMIA VIRUS

Project Details

Description

Retroviruses are RNA viruses capable of inducing various diseases
including cancers and immunodeficiencies. Many retroviruses cause
cellular transformation because they carry oncogenes transduced from
cellular genes. Due to their high efficiency in transferring genes,
retroviral vectors, ironically, are a preferred means of introducing genes
into cells for gene therapy. The long-term goal of this proposal is to
understand on the molecular level the mechanism by which Murine Leukemia
Viruses (MuLV) choose and enter their host cells. The viral gene products
which are known to be required for the entry of the virus into the cells
(env gene products) will be studied genetically and biochemically.
Identification of the various functional domains of the env gene products
provides the basis for future experiments aimed at targeting the entry of
the virus to specific cell types and facilitates the use of retroviruses
for gene therapy. The env gene products from two MuLV isolates with differing host-range
will be analyzed and compared. Linker-insertion mutations will be
generated throughout the env gene of the Moloney ecotropic MuLV, which
only infects rodent cells, as well as the amphotropic 4070A isolate, which
can infect many mammalian species. The effects of the mutations on the
viral life-cycle will be determined. Functional domains within the
proteins will be localized by the clustering of mutations with identical
phenotypes. Regions required for correct processing and transport to the
cell surface, association with the viral particle, syncytium formation,
and receptor binding may be identified. A second approach to identify regions required for receptor binding and
recognition will involve the generation of hybrid amphotropic/ecotropic
env gene products. Variations within the env gene alter the host-range of
the virus and direct the entry using differing host-cell receptors.
Hybrid env molecules in which the majority of the amphotropic env gene has
replaced the ecotropic gene has produced virus with the amphotropic host-
range. Using cloning techniques, various sections of the amphotropic env
gene will be systematically introduced into the ecotropic backbone. The
host-range of the hybrid gene product will be examined and regions
required for the receptor binding and tropism will be determined. env gene products with altered oligosaccharide moieties will be generated
to address the role of the multiple glycosylations. The potential
glycosylation sites will be changed using oligonucleotide-directed
mutagenesis. The effects of the loss of the individual sites as well as
multiple glycosylation sites will be examined. The final processed form of the env gene product contains two proteins, SU
and TM, are covalently bound through a disulfide bridge. the cysteine
residue involved in this bond in the TM protein will be identified.
StatusFinished
Effective start/end date1/1/907/31/14

Funding

  • National Institutes of Health: $289,225.00
  • National Institutes of Health: $24,841.00
  • National Institutes of Health: $278,009.00
  • National Institutes of Health: $244,210.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $237,001.00
  • National Institutes of Health: $286,425.00
  • National Institutes of Health: $118,451.00
  • National Institutes of Health: $286,425.00
  • National Institutes of Health: $264,140.00
  • National Institutes of Health: $289,225.00
  • National Institutes of Health: $286,425.00
  • National Institutes of Health: $159,382.00
  • National Institutes of Health: $55,659.00
  • National Institutes of Health
  • National Institutes of Health: $135,332.00
  • National Institutes of Health: $136,597.00
  • National Institutes of Health
  • National Institutes of Health: $274,237.00
  • National Institutes of Health: $61,330.00
  • National Institutes of Health: $282,428.00

ASJC

  • Medicine(all)

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