NEW RETROVIRAL RECEPTORS/HOST RESISTANCES

  • Kabat, David, (PI)

Project: Research project

Description

Until recently, only several cellular receptors for retroviruses had been molecularly cloned and functionally identified. However, using a powerful new strategy we recently cloned novel receptors from a human T lymphocyte cDNA library, including a common receptor (X-receptor) for xenotropic and polytropic host-range groups of murine leukemia viruses (MLVs), a receptor (C-receptor) for feline leukemia virus type C (FeLV-C), which causes prevalent aplastic amenias in cats, and the R-receptor for RD 114 feline endogenous virus that also mediates infections by baboon endogenous virus (BaEV), avian reticuloendotheliosis virus (REV) and the primate type D retroviruses that cause severe immunodeficiencies and have been reported as an opportunistic infection in a human patient with AIDS. In addition, we determined that the R-receptor is the broad specificity neutral amino acid transporter BO, that the X-receptor is involved in Na+-phosphate cotransport, and that the C-receptor is a member of the large MFS (major facilitator superfamily) of transporters. These discoveries and methods provide opportunities for improved understanding of these and other highly pathogenic retroviruses. We propose: (i) Isolate X-, R-, and C- receptor homologues from mice and use human-mouse chimeras and site-directed mutants to identify active sites in these receptors and the mechanisms for murine resistances to infections. (ii) Conversely, use chimeras and site-directed mutants of closely related xenotropic and polytropic MLV envelope glycoproteins to identify amino acid(s) that control the differential infectivity of these viruses for various strains of mice. Thereby, identify the basis for this xenotropism at the levels of both the virus and the X-receptor. (iii) Clone critically important cell surface receptors for other retroviruses, including FeLV-A. (iv) Thoroughly analyze the normal cellular functions of the X-, R-, and C- receptors. Study the effects of infection on these functions and the pathogenic consequences of these functional perturbations. Use this functional information to optimize transduction efficiencies for gene therapy. These investigations build on a technological breakthrough and will substantially expand our understanding of human and animal retroviral diseases and of host resistance mechanisms.
StatusFinished
Effective start/end date2/5/001/31/06

Funding

  • National Institutes of Health: $261,742.00
  • National Institutes of Health: $246,822.00
  • National Institutes of Health: $260,293.00
  • National Institutes of Health: $254,171.00
  • National Institutes of Health: $269,541.00

Fingerprint

Retroviridae
Virus Receptors
Murine Leukemia Viruses
Viruses
Avian Reticuloendotheliosis Viruses
Betaretrovirus
Neutral Amino Acid Transport Systems
Infection
Feline Leukemia Virus
Animal Diseases
Disease Resistance
Papio
Host Specificity
Felidae
Opportunistic Infections
Cell Surface Receptors
Gene Library
Genetic Therapy
Primates
Catalytic Domain

ASJC

  • Medicine(all)