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Prevention of viral infection via modification of virus or cells with methoxypoly (ethylene glycol)

University of British Columbia

Viral entry into cells is typically mediated by specific interactions between viral proteins and cell surface receptors. Recent pharmacological methods have attempted to exploit this specificity. For example, the interaction of rhinoviruses with ICAM-1 (its cell receptor) can be inhibited by either free zinc or soluble ICAM-1. However, this and other approaches are highly virus specific. Therefore a broad-spectrum method of preventing viral infections is needed. One potential nonspecific method of preventing viral infections is through the modification of host cells with a nontoxic physical barrier. It is my hypothesis that this may be accomplished by the covalent derivatization of cell membranes with methoxypoly(ethylene glycol) [mPEG]. Our previous research demonstrated that covalent modification of mammalian cells with activated mPEG produced a protective barrier that functioned, in part, as a molecular sieve. While small molecules (e.g., water and glucose) readily pass through, larger molecules (e.g., antibodies), particles (e.g., immune complexes) and cells were excluded from interacting with membrane components. My study further extended these findings to models of viral pathogenesis. Five viruses were employed: Simian virus 40 [SV40], Theiler's murine encephalomyelitis virus [TMEV], mouse adenovirus [MAV], rat coronavirus [RCV] and cytomegalovirus [CMV]. Importantly, these viruses varied in mode of entry, size and structure. As demonstrated in this thesis, modification of either the virus or target cell effectively blocked viral infection. For example, cells challenged with unmodified SV40 were 47% infected at 24hours while < 4 and 0% of cells modified with 2.4 and 15 mM 5 kDa cyanuric chloride activated mPEG (CmPEG) were infected, respectively. The broad spectrum effects of mPEG grafting were demonstrated by the findings that modification of host cells with only 0.2 mM activated mPEG (5 kDa) resulted in a 95%, 78% and 47% reduction in plaque formation compared to control cells challenged with RCV, MAV and TMEV, respectively. Further studies were conducted to determine the effects of reaction time, temperature, polymer size and linker chemistry on the antiviral efficacy of mPEG gafting. In summary, these studies show that mPEG modification of viruses and/or host cells is a potent and broad spectrum method of preventing viral infection.

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2009-12-23

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http://hdl.handle.net/2429/17253

Pathology

University of British Columbia

UBCV

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