Cell signalling and feline immunodeficiency virus growth and latency

• Main Author: Chan, Chi Ngai
• Published: University of Glasgow 2013
• Subjects: QR355 Virology
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.566450

The replication of CD4+ T cell-tropic retroviruses such as the human immunodeficiency virus-1 (HIV-1) and the feline immunodeficiency virus (FIV) is intricately linked to host cell signalling and activation status. This intimate relationship between the viruses and their respective hosts plays crucial roles in the pathogenesis of each virus. Focusing on FIV, this thesis examined several questions relating to virus replication and cell signalling. Firstly, the possible cell stimulatory effect when FIV Env binds to its primary receptor CD134 was investigated and results suggested that FIV does not trigger CD134 signalling. Next the activation status of susceptible CD4+ T cells was manipulated to study FIV latency and it was shown that by removing exogenous supplement of the cytokine interleukin-2 (IL-2) from MYA-1 feline CD4+ T cells 24 hours before infection, productive FIV replication is down-regulated such that only a very low level of ongoing virus replication can be detected among the IL-2-depleted cells with a sensitive qPCR assay. The phorbol esters PMA and Prostratin can stimulate high level of productive infection from these IL-2-depleted MYA-1 cells and this is mediated by a protein kinase C (PKC) dependent mechanism. Furthermore, productive replication of FIV in the presence of IL-2 is blocked by stimulation of PKC with phorbol esters, which is analogous to findings of similar experiments with HIV-1. However, inhibition of viral replication is not at the level of viral entry, contrary to the findings of HIV-1 studies. The mechanism behind the Prostratin-mediated inhibition of FIV remains elusive. It was also discovered that ‘early’ and ‘late’ strains of FIV responded differently to cell signalling manipulation and an attempt was made to map the viral genome region(s) responsible. Preliminary data showed that both env and the 5’UTR may mediate the inter-strain differences in replication dynamics. Overall this thesis shows the complete dependency of FIV on host cell signalling, in particular optimum PKC activation to achieve productive viral replication. This may reflect the tropism of the virus. The similarities between HIV-1 and FIV replication and latency support the notion of using FIV and the cat as a model for HIV-1 latency in the development of novel therapeutic measures to eradicate hidden HIV-1 from the host. However, more research is required to fully characterise the differences between HIV-1 and FIV biology.