Multiple Virus

This chapter has shown that the host has multiple mechanisms for detecting viruses, while viruses have evolved numerous immunomodulatory strategies in order to achieve a more successful life cycle. Most components of the iimate immune system are targeted by multiple viruses for evasion or subversion and discoveries in this field continue at a pace which sometimes outruns and even informs the discovery of innate immune mechanisms. With the on going exploration of immunomodulation by viruses much more will be unearthed about the unknown components of antiviral signalling. In addition these studies could potentially herald more antiviral treatments. 

Can any number of identical subunits be accommodated in the asymmetric unit while preserving specificity of interactions within an icosahedral arrangement This question was answered by Don Caspar then at Children s Hospital, Boston, and Aaron Klug in Cambridge, England, who showed in a classical paper in 1962 that only certain multiples (1, 3, 4, 7...) of 60 subunits are likely to occur. They called these multiples triangulation numbers, T. Icosahedral virus structures are frequently referred to in terms of their trian-gulation numbers a T = 3 virus structure therefore implies that the number of subunits in the icosahedral shell is 3 x 60 = 180. 

Small spherical viruses have a protein shell around their nucleic acid that is constructed according to icosahedral symmetry. Objects with icosahedral symmetry have 60 identical units related by fivefold, threefold, and twofold symmetry axes. Each such unit can accommodate one or severed polypeptide chains. Hence, virus shells are built up from multiples of 60 polypeptide chains. To preserve quasi-equivalent symmetry when packing subunits into the shell, only certain multiples (T = 1, 3, 4, 7...) are allowed. 

Harrison, S.C. Multiple modes of subunit association in the structures of simple spherical viruses. Trends Biochem. Sci. 9 345-351, 1984. 

The immune system can malfunction either by attacking itself or the body (which happens in auto-immune diseases such as multiple sclerosis) or by being weakened itself in some way (such as what occurs as a result of the AIDS virus). 

For the pathogenesis of multiple sklerosis, autoimmune T-lymphocy tes play a predominant role, which are directed against components of the neural myelin sheath. T-lymphocy tes by secreting cytokines such as interferon y maintain the chronic inflammation which destructs the myelin sheath. Also cytotoxic T-lymphocytes may participate directly. The cause of multiple sklerosis is unknown. Significantly increased antibody titers against several vitusses, mostly the measles virus, point to a (latent) virus infection initiating the disease. 

Benzalkoilium (Zephiran) is a rapid-acting preparation with a moderately long duration of action. It is active against bacteria and some viruses, fungi, and protozoa Benzalkonium solutions are bacteriostatic (slow or retard the multiplication of bacteria) or bactericidal (destroy bacteria), depending on their concentration. 

Pharmacokinetic studies demonstrated good oral bioavailability of maraviroc and a terminal half-life of 16-23 h following multiple dosing (Abel et al. 2003 Walker et al. 2005). Single doses of up to 900 mg and multiple doses of up to 300 mg BID for 28 days were well tolerated (Abel et al. 2003 Russell et al. 2003 Walker et al. 2005). In Phase 2a studies, treatment-naive HIV-1 patients with R5 virus who received maraviroc monotherapy at doses ranging from 25 mg QD to 300 mg BID for 10 days experienced a median viral load reduction of 1.64 log jg copies/mL and... 

The multiple sites that serve as origins for DNA replication in eukaryotes are poorly defined except in a few animal viruses and in yeast. However, it is clear that initiation is regulated both spatially and temporaUy, since clusters of adjacent sites initiate rephcation synchronously. There are suggestions that functional domains of chromatin replicate as intact units, implying that the origins of rephcation are specificaUy located with respect to transcription units. 

EAE experimental autoimmune encephalomyehtis, MHVmmmt hepatitis virus, LCMVlymphocytic choriomeningitis virus, MS multiple sclerosis, IWWWest Nile virus, TBEVtick-borne encephalitis virus... 

Cheeran MC, Hu S, Sheng WS, Rashid A, Peterson PK, Lokensgard JR (2005) Differential responses of human brain cells to West Nile virus infection. J Neurovirol 11 512-524 Cudrici C, Ito T, Zafranskaia E, Niculescu F, Mullen KM, Vlaicu S, Judge SI, Calabresi PA, Rus H (2007) Dendritic cells are abundant in non-lesional gray matter in multiple sclerosis. Exp Mol Pathol 83 198-206... 

Franklin RJ (2002) Why does remyehnation fail in multiple sclerosis Nat Rev Neurosci 3 705-714 Fratkin JD, Leis AA, Stokic DS, Slavinski SA, Geiss RW (2004) Spinal cord neuropathology in human West Nile virus infection. Arch Pathol Lab Med 128 533-537 Frohman EM, Racke MK, Raine CS (2006) Multiple sclerosis - the plaque and its pathogenesis. N Engl J Med 354 942-955... 

Hunsperger EA, Roehrig JT (2006) Temporal analyses of the neuropathogenesis of a West Nile virus infection in mice. J Neurovirol 12 129-139 Huseby ES, Liggitt D, Brabb T, Schnabel B, Ohlen C, Goverman J (2001) A pathogenic role for myelin-specific CD8(-I-) T cells in a model for multiple sclerosis. J Exp Med 194 669-676... 

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