The overall aim of this project is to identify the cellular receptor(s) for the feline lentiviruses and to examine the role of the virus-receptor interaction in the pathogenesis of AIDS. The project will build upon our earlier work demonstrating that CXCR-4 is the major, if not sole, co-receptor for the feline immunodeficiency virus (FIV) lentivirus of the domestic cat. In the domestic cat, FIV infection induces an immunodeficiency syndrome similar to AIDS in HIV- infected humans. In the proposed studies, we will ask whether receptor usage determines pathogencity of feline lentiviruses in domestic vs. non-domestic cats as is postulated for receptor usage and pathogenicity in primate lentiviral systems. Several lines of evidence suggest that primary strains of FIV require the co-expression of another cell surface molecule (perhaps analogous to the HIV receptor CD4) in addition to CXCR-4 in order to infect all target cells.
Aim 1 will determine whether FIV utilizes a primary receptor beside CXCR-4 for infection of feline cells. We will use retroviral pseudotypes to screen cDNA libraries for additional receptor(s) and/or co- receptors and the function of the molecule(s) will be characterised.
Aim 2 will examine the link between receptor-usage and pathogenicity. We will ask whether receptor usage varies among feline lentivirus isolates, i.e.: (a) isolates characterized as pathogenic vs. non-pathogenic in experimental studies; (b) isolates obtained from asymptomatic vs. symptomatic naturally infected cats; and (c) isolates transmitted via different routes in experimental studies.
Aim 3 will investigate whether non-domestic vs. domestic cat lentiviruses use different vs. common viral receptors. The lentiviruses of the non-domestic cats appear to be more ancient and more adapted to their host species than is FIV to the domestic cat. We will investigate whether receptor-usage is a determinant of host-adaptation. These studies will elucidate the cellular receptor(s) for the feline lentiviruses, determine whether changes in receptor usage relate to pathogenicity, and forecast the future of both FIV/domestic cat and HIV/human receptor-virus evolutionary outcomes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049765-02
Application #
6532866
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Wassef, Nabila M
Project Start
2001-08-20
Project End
2004-06-30
Budget Start
2002-08-01
Budget End
2003-06-30
Support Year
2
Fiscal Year
2002
Total Cost
$190,000
Indirect Cost
Name
University of Glasgow
Department
Type
DUNS #
City
Scotland
State
Country
United Kingdom
Zip Code
G12 8-QQ
Teixeira, Bruno M; Hagiwara, Mitika K; Cruz, Juliano C M et al. (2012) Feline immunodeficiency virus in South America. Viruses 4:383-96
Teixeira, B M; Logan, N; Samman, A et al. (2011) Isolation and partial characterization of Brazilian samples of feline immunodeficiency virus. Virus Res 160:59-65
Teixeira, Bruno Marques; Logan, N; Cruz, J C M et al. (2010) Genetic diversity of Brazilian isolates of feline immunodeficiency virus. Arch Virol 155:379-84
Kraase, Martin; Sloan, Richard; Klein, Dieter et al. (2010) Feline immunodeficiency virus env gene evolution in experimentally infected cats. Vet Immunol Immunopathol 134:96-106
McEwan, William A; Schaller, Torsten; Ylinen, Laura M et al. (2009) Truncation of TRIM5 in the Feliformia explains the absence of retroviral restriction in cells of the domestic cat. J Virol 83:8270-5
Willett, Brian J; McMonagle, Elizabeth L; Logan, Nicola et al. (2009) Enforced covalent trimerisation of soluble feline CD134 (OX40)-ligand generates a functional antagonist of feline immunodeficiency virus. Mol Immunol 46:1020-30
Willett, Brian J; Hosie, Margaret J (2008) Chemokine receptors and co-stimulatory molecules: unravelling feline immunodeficiency virus infection. Vet Immunol Immunopathol 123:56-64
Willett, Brian J; McMonagle, Elizabeth L; Logan, Nicola et al. (2008) A single site for N-linked glycosylation in the envelope glycoprotein of feline immunodeficiency virus modulates the virus-receptor interaction. Retrovirology 5:77
McEwan, William A; McMonagle, Elizabeth L; Logan, Nicola et al. (2008) Genetically divergent strains of feline immunodeficiency virus from the domestic cat (Felis catus) and the African lion (Panthera leo) share usage of CD134 and CXCR4 as entry receptors. J Virol 82:10953-8
Willett, Brian J; McMonagle, Elizabeth L; Logan, Nicola et al. (2007) Probing the interaction between feline immunodeficiency virus and CD134 by using the novel monoclonal antibody 7D6 and the CD134 (Ox40) ligand. J Virol 81:9665-79

Showing the most recent 10 out of 16 publications