Gray, E.R.; (2008) Route of entry-dependent blocks to retroviral replication. Doctoral thesis , University of London.

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Abstract

Restriction factors are endogenous cellular proteins that block retroviral replication at specific points in the life cycle. Those identified so far include Fvl, Trim5a and TrimCyp. Their characterisation has extended knowledge of retroviral and cellular functions, and has added a new branch to innate immunity. Retroviral susceptibility to Fvl and Trim5a is determined by its capsid, and is manifested in a pre- (Trim5a, TrimCyp) or post- (Fvl) reverse transcription block to replication. Other blocks to replication have been postulated. For example, a novel anti-viral factor, Lv2, is thought to block replication of several primary isolates of HIV-2 in some cell lines. Knowledge of the early steps of virus replication, between entry and nuclear import, is critical to understanding restriction. The intention of the studies described in this thesis was to determine whether alternative routes of virus trafficking might affect susceptibility to Fvl and Trim5a, as well as to the putative Lv2. A system of two receptors was used, Tva800 and Tva950 both permit entry via ASLV envelope protein, but take the virus into the cell by two different endocytic mechanisms. The pathways traversed after binding to Tva800 and Tva950 were investigated and shown not to reroute virions around restriction mediated by Fvl and Trim5a. When virus titration curves were analysed, a distinctive pattern emerged suggesting that entry via Tva800, but not Tva950, requires engagement of more than one receptor- envelope pair. The block to replication caused by the putative factor Lv2 was also analysed. It was concluded that a combination of low surface CD4 expression and poor receptor engagement are the cause of low viral titres in some cell lines, rather than a cellular anti-viral factor per se.

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