Genetic Characterization

Herpes simplex virus TK is involved in 95% of HSV resistance to ACV. It is a 376-amino acid protein, encoded by a gene of 1128 bp (UL 23). It exhibits an ATP binding site (amino acid 51 to 63) and a nucleoside binding site (amino acid 168 to 176) and six regions conserved among herpesviridae TK (amino acid 50 to 66, 79 to 91,162 to 178, 212 to 226 and 281 to 292). Figure 1 presents the localization of mutations reported in ACV-sensitive and ACV-resistant HSV clinical isolates, in relation to the localization of active and conserved sites of the enzyme. These data were obtained by genetic characterization of about 70 ACV-resistant HSV isolates and 30 ACV-sensitive HSV isolates.[24,25] These studies revealed a large degree of polymorphism in the HSV TK gene. The mutations unrelated to resistance are located throughout the gene but

^ conserved regions among herpesviridae TK Q GC homopolymer repeats b.s. : binding site Ns : nucleoside

Fig. 1 Thymidine kinase mutations reported in ACV-sensitive and ACV-resistant HSV clinical isolates.

^ conserved regions among herpesviridae TK Q GC homopolymer repeats b.s. : binding site Ns : nucleoside

Fig. 1 Thymidine kinase mutations reported in ACV-sensitive and ACV-resistant HSV clinical isolates.

they are almost all located outside TK active and conserved sites. Gene polymorphism is four times higher for HSV 1 than for HSV 2.[26] Among mutations that could be associated with resistance, half were nucleotide insertion or deletion, and half were nucleotide substitution.[27-29] Nucleotide insertions or deletions are responsible for a frameshift and the synthesis of a truncated, nonfunctional TK. They are often located in homopolymer repeats of guanines or cytosines that are mutational hot spots. Mutations were found several times in repeats located at codon 92 (five guanines) and at codon 146 (seven guanines). The frameshift mutation in the 7Gs homopolymer of codon 146 is the most frequent mutation reported in ACV-resistant HSV isolates.[21,27,28,30] Numerous nucleo-tide substitutions, most often recovered in conserved regions of the TK gene, have been described in ACV-resistant clinical HSV strains, but some are reported more frequently as the substitution of arginine 176 of HSV 1 and 177 of HSV 2, and the mutation of amino acid 336.[24] Herpes simplex virus DNA polymerase is a 1235-amino acid protein encoded by a 3705-bp gene (UL 30). It includes eight conserved regions in comparison with cellular or viral DNA polymerases; these regions are labeled I to VII according to their degree of conservation (region I being the most conserved), plus one region called A. DNA polymerase mutations associated with resistance are related to genetic characterization of about 15 resistant strains either isolated from patients[21,31] or selected in vitro.[23,32,33] As for TK, these mutations are mainly located in the conserved regions, especially in regions II and III which include more than 40% of the mutations reported so far in the DNA polymerase gene.

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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