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Factors affecting replication and cross-species transmission of feline immunodeficiency virus

McEwan, William (2010) Factors affecting replication and cross-species transmission of feline immunodeficiency virus. PhD thesis, University of Glasgow.

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Abstract

In order to successfully invade a new species, lentiviruses must overcome restriction factors, dominant blocks to replication, and be able to make use of available host factors such as entry receptors for replication. Human immunodeficiency virus (HIV-1) infection is blocked at a post-entry stage by rhesus macaque TRIM5α, an effect that is enhanced by host factor cyclophilin A (CypA), but largely evades restriction by the human TRIM5α variant. HIV-1 replication is also inhibited by simian APOBEC3G but is able to evade restriction by human APOBEC3G by inducing its degradation through expression of accessory protein Vif. Viral entry and tissue tropism are determined by an interaction of the viral Env glycoprotein with a cell surface receptor and a seven transmembrane domain co-receptor. The feline immunodeficiency virus (FIV) infects diverse felid species including the African lion, where infection has likely been endemic since at least the late Pleistocene, and the domestic cat, a more recent host. For domestic cat strains of FIV (FIV-Fca), entry is mediated by host proteins CD134 and CXCR4, but the identity of receptors in non-domestic strains of FIV is unknown. This thesis demonstrates that two strains of FIV isolated from lions (FIV-Ple subtypes B and E) differ in their receptor tropism and that subtype E shares entry receptors with FIV-Fca. The findings suggest that alternative receptor usage is a strategy employed by FIV in this species and has implications for the disputed pathology and tissue tropism of infection in African lions. Next, we tested the hypothesis that species which have harboured lentiviral infection for a long time are better able to prevent viral replication than recent hosts. Whilst we found that TRIM5α is non-functional in all felid species tested, evidence of potent APOBEC3 activity was found and, in lion cells, potently restricts production of infectious FIV. Moreover, lion primary T-cells prevent replication of diverse FIV strains and restrict primate lentiviruses at post-entry stages, suggesting that co-evolution with lentiviruses has driven the selection of broad-ranging restriction factors. Structural and biophysical analyses suggest that whilst FIV’s interaction with CypA appears to be conserved in affinity with HIV-1, the interaction does not appear to be crucial for replication and, in the absence of restriction by TRIM5α, the role of the capsid-CypA interaction is discussed. Overall the study explains the permissivity of domestic cat cells to retroviral infection and identifies FIV infection of lions as an example of host adaptation driven by current lentiviral infection.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: FIV, feline immunodeficiency virus, lentivirus, TRIM5, TRIM5alpha, retroviral restriction, restriction factor, Env, Vif, capsid, APOBEC, lion, Panthera leo, domestic cat, Felis catus, cyclophilin A, CypA, Ranbp2
Subjects: Q Science > QR Microbiology > QR355 Virology
Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Veterinary Medicine
Supervisor's Name: Willett, Prof. Brian J.
Date of Award: 2010
Depositing User: Mr William A McEwan
Unique ID: glathesis:2010-1388
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 22 Dec 2009
Last Modified: 10 Dec 2012 13:38
URI: http://theses.gla.ac.uk/id/eprint/1388

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