Keckesova, Z.; (2007) A study of host factors influencing retroviral infectivity. Doctoral thesis , University of London.

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Abstract

While mammalian cells provide many of the molecules and machinery required by retroviruses to successfully achieve their replication cycle, they have also developed specific defences to protect themselves against viral infection. Existence of these antiviral "restriction" factors accounts for the limited ability of viruses to spread from one species to another. If a new virus becomes successfully established in its new host then it can cause serious disease, as is the case in the HIV pandemic. It is thus important to identify and understand how these mammalian protective factors work, to understand the molecular mechanisms involved and how viruses can evade them. The aim of my PhD thesis is to better understand the role of these restriction factors in innate immunity. My work in the last 3 years has been to examine various aspects of retroviral restriction by a cellular protein called TRIM5alpha. The first part of my PhD thesis shows that the Lvl and Refl class of restriction factors are species-specific variants of TRIM5ct, a factor that was shown to block HIV-1 infection in Rhesus macaque cells. Differential splicing of TRIM5 transcripts results in the production of several isoforms that lack the TRIM5ot C-terminal B30.2 domain. To examine the contribution of these short TRIM5 splice variants to antiviral activity I cloned the TRIM58 isoform. I have shown that expression of human TRIM58 in cat and human cells had a dominant negative effect on the activity of co-expressed human TRIM5a. The second part of my PhD thesis focuses on the role of the peptidyl prolyl isomerase enzyme cyclophilin A in TRIM5a's antiviral activity. It shows that cyclophilin A renders HIV-1 sensitive to restriction by TRIM5a in cells from Old World monkeys and that in human cells the effects of cyclophilin A on HIV-1 infection are independent of TRIM5a. The third part of my thesis investigates the effects of arsenic trioxide, a drug that modifies the behaviour of the TRIM protein PML (TRIM 19), on TRIM5ct mediated restriction. By using molecular biology, biochemistry and microscopy I showed that arsenic influences retroviral replication through its effect on TRIM5a and that it causes the degradation of this restriction factor.

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