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"Measles immunization has been introduced since 1960, thereby markedly reducing the number of cases in developed countries. However, measles epidemics still occur even in developed countries. In the United States, in 1988-1992 an increase in the number of measles cases reaching 50,000 cases was reported. Some of these cases occurred in previously immunized patients. This was thought to be caused by genetic mutation of the measles virus, aside from weaknesses of the vaccine and low immunization coverage.Since measles immunization was employed in Indonesia, the number of measles patients has decreased. However, epidemics are still frequently reported. About 15-30% of reported cases occurred in those previously immunized, raising the question of whether a genetic difference exists between the wild-type measles virus circulating in Indonesia and the vaccine virus being used. Such a difference may lead to the differences in the antigenicity of the wild-type and vaccine viruses, rendering the resulting antibody incapable of neutralizing the wild-type viruses. Based on the above, this study is aimed to demonstrate the extent of genetic and antigenic differences between the wild-type and vaccine measles viruses.We conducted an experimental laboratory study to sequence the N, H, and F genes of the wild-type measles viruses (G2, G3, and D9) and the CAM-70 vaccine virus. To show antigenic differences, the wild-type viruses (G2, G3, and D9) and the CAM-70 and Schwarz viruses were injected to BALB/c mice. Serum antibodies of the mice were analyzed using ELISA, cross-neutralization test, and immunoblotting using antigens from the respective viruses.Results of this study showed that the wild-type and the vaccine viruses differ in the sequence of the N gene by 73-79 nucleotides, resulting in amino acid substitution of 17-24 residues; the H gene by 60-99 nucleotides, resulting in amino acid substitution of 13-29 residues; the F gene by 71-88 nucleotides, resulting in amino acid substitution of 4-3 I residues. Differences between the wild-type and the CAM-70 and Schwarz vaccine viruses were also found in the epitope site of the CTL and antibodies, which are important to virus antigenicity.We conclude that a significant difference in antigenicity exists between the wild-type measles viruses circulating in Indonesia with the CAM-70 measles virus. We also found the immunogenicity of the CAM-70 and Schwarz vaccine viruses to be lower than that of the wild-type viruses."

"ABSTRAKResistensi terhadap lamivudin merupakan masalah yang sering dihadapi pada pengobatan penderita hepatitis B. Resistensi lamivudin biasanya dihubungkan dengan faktor virus yaitu mutasi gen P terutama di daerah YMDD, sedangkan penelitian pada faktor pejamu (host) belum pernah dilakukan. Penelitian ini bertujuan : 1) Untuk mengetahui peranan gen dCK pejamu (host) yang mengkode enzim deoksisitidin kinase pada resistensi lamivudin 2) Untuk mengetahui peranan gen P virus hepatitis B yang mengkode polimerase/reverse transcriptase pada resistensi lamivudin. Penelitian ini menggunakan metode Polymerase Chain Reaction (PCR) dan direct sequencing. Hasil penelitian menunjukkan bahwa gen dCK (ekson 2) relatif conserved. Mutasi yang tidak signifikan (G33W) ditemukan hanya pada satu pasien yang sensitif terhadap lamivudin, sedangkan pada kelompok pasien yang resisten terhadap lamivudin dan kelompok populasi nonnal tidak ditemukan mutasi. Penelitian pada gen P (domain RT) virus hepatitis B menemukan 1 (6,25 %) mutasi pada domain B yaitu L526M (rt LISOM) dan 6 (37,5%) mutasi pada domain C yaitu mutan YMDD yang terdiri atas 5 (3l,25%) mutan M5501 (rt M2040 dan 1 (6,25%) mutan M550V (rt M20-4V). Satu mutan MSSOV juga mengalami mutasi L526M. Pada penelitian ini juga ditemukan mutasi baru pada domain A yang belum pemah dipublikasikan yaitu Y487F (rt YI4IF), D480N (rt Dl34N) dan N485S (rt Nl39S). Mutan Y487F ditemukan pada 5 pasien (3l,25%) yang sama persis dengan mutasi MSSOI. Domain A dan C mempunyai peranan pada binding nukleosida trifosfal, sehingga diperkirakan mutasi baru yang ditemukan pada domain A juga mempunyai kontribusi terhadap terjadinya resistensi lamivudin. Virus yang mengalami mutasi L526M + MSSZV tidak menunjukkan mutasi pada Y487F, tetapi mengalami mutasi pada D48ON dan N485S. Kesimpulan yang dapat diambil dari penelitian ini adalah : 1) Pada level genetik tidak terjadi perubahan atau mutasi gen dCK (ekson 2) yang berhubungan dengan resistensi lamivudin. 2) Pada gen P (domain RT) virus hepatitis B terdapat mutasi pada domain A, B dan C yang berhubungan dengan resistensi terhadap lamivudin.

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Abstract

The resistance against lamivudine treatment in hepatitis B patients is a problem frequently encountered by physicians. Lamivudine resistance is usually associated with viral mutations especially in the YMDD region of P gene, the involvement of host factors however, was not studied yet so far. This investigation is designed to determine either host or viral factors responsible responsible for lamivudine resistance. The aim of this study are : 1) To understand the involvement of host dCK gene which code for deoxycytidine kinase in lamivudine resistance. 2) To understand the involvement of viral P gene which code for polymerase/reverse transcriptase in lamivudine resistance. The investigation was performed by means of Polymerase Chain Reaction (PCR) and direct sequencing methods. The results indicate that dCK gene (exon 2) is relatively conserved. Unsignificant mutation (G33W) was found in only one patient who was sensitive to lamivudine treatment."

"ABSTRAKResistensi terhadap lamivudin merupakan masalah yang sering dihadapi pada pengobatan penderita hepatitis B. Resistensi lamivudin biasanya dihubungkan dengan faktor virus yaitu mutasi gen P terutama di daerah YMDD, sedangkan penelitian pada faktor pejamu (host) belum pernah dilakukan. Penelitian ini bertujuan : 1) Untuk mengetahui peranan gen dCK pejamu (host) yang mengkode enzim deoksisitidin kinase pada resistensi lamivudin 2) Untuk mengetahui peranan gen P virus hepatitis B yang mengkode polimerase/reverse transcriptase pada resistensi lamivudin. Penelitian ini menggunakan metode Polymerase Chain Reaction (PCR) dan direct sequencing.Hasil penelitian menunjukkan bahwa gen dCK (ekson 2) relatif conserved. Mutasi yang tidak signifikan (G33W) ditemukan hanya pada satu pasien yang sensitif terhadap lamivudin, sedangkan pada kelompok pasien yang resisten terhadap lamivudin dan kelompok populasi nonnal tidak ditemukan mutasi. Penelitian pada gen P (domain RT) virus hepatitis B menemukan 1 (6,25 %) mutasi pada domain B yaitu L526M (rt LISOM) dan 6 (37,5%) mutasi pada domain C yaitu mutan YMDD yang terdiri atas 5 (3l,25%) mutan M5501 (rt M2040 dan 1 (6,25%) mutan M550V (rt M20-4V). Satu mutan MSSOV juga mengalami mutasi L526M. Pada penelitian ini juga ditemukan mutasi baru pada domain A yang belum pemah dipublikasikan yaitu Y487F (rt YI4IF), D480N (rt Dl34N) dan N485S (rt Nl39S). Mutan Y487F ditemukan pada 5 pasien (3l,25%) yang sama persis dengan mutasi MSSOI. Domain A dan C mempunyai peranan pada binding nukleosida trifosfal, sehingga diperkirakan mutasi baru yang ditemukan pada domain A juga mempunyai kontribusi terhadap terjadinya resistensi lamivudin. Virus yang mengalami mutasi L526M + MSSZV tidak menunjukkan mutasi pada Y487F, tetapi mengalami mutasi pada D48ON dan N485S. Kesimpulan yang dapat diambil dari penelitian ini adalah : 1) Pada level genetik tidak terjadi perubahan atau mutasi gen dCK (ekson 2) yang berhubungan dengan resistensi lamivudin. 2) Pada gen P (domain RT) virus hepatitis B terdapat mutasi pada domain A, B dan C yang berhubungan dengan resistensi terhadap lamivudin.

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Abstract

The resistance against lamivudine treatment in hepatitis B patients is a problem frequently encountered by physicians. Lamivudine resistance is usually associated with viral mutations especially in the YMDD region of P gene, the involvement of host factors however, was not studied yet so far. This investigation is designed to determine either host or viral factors responsible responsible for lamivudine resistance. The aim of this study are : 1) To understand the involvement of host dCK gene which code for deoxycytidine kinase in lamivudine resistance. 2) To understand the involvement of viral P gene which code for polymerase/reverse transcriptase in lamivudine resistance. The investigation was performed by means of Polymerase Chain Reaction (PCR) and direct sequencing methods.

The results indicate that dCK gene (exon 2) is relatively conserved. Unsignificant mutation (G33W) was found in only one patient who was sensitive to lamivudine treatment; while no mutations were fotmd in either patients resistance agains lamivudine treatment or normal population. A study on P gene (RT domain) of hepatitis B virus have found l (6,25 %) mutation on B domain as L526M (rt LISOM) and 6 (37.5 %) mutations on C domain as YMDD mutants composing of 5 (31.25 %) mutant M5501 (rt M204l) and 1 (6.25 %) mutant MSSOV (rt M204V). A mutant of MSSOV is also mutate on L526M. This study also discovered new mutations in A domain which have unpublished yet; thhey are Y487F (rt Y141F), D430N (rt D131N) and N485S (rt Nl39S). Y-487F mutants were found in 5 patients (31.25 %) who definitely similar to mutation of M550I. The A and C domain are responsible for nucleside triphosphate binding, therefore the mutation found in A domain is also considered to contribute to lamivudine resistance manifestation. Virus with mutation of L526 + M55 OV did not indicate mutation in Y487F, but mutated in D480N and N485S otherwise. The conclusion of this study are : 1) There are no changes or mutations of dCK gene (exon 2) associate to lamivudine resistance. 2) There are mutations on hepatitis B virus P gene (RT domain) present on A, B and C domain which are associated with resistance to lamivudine treatment."

"Measles immunization has been introduced since 1960, thereby markedly reducing the number of cases in developed countries. However, measles epidemics still occur even in developed countries. In the United States, in 1988-1992 an increase in the number of measles cases reaching 50,000 cases was reported. Some of these cases occurred in previously immunized patients. This was thought to be caused by genetic mutation of the measles virus, aside from weaknesses of the vaccine and low immunization coverage. Since measles immunization was employed in Indonesia, the number of measles patients has decreased. However, epidemics are still frequently reported. About 15-30% of reported cases occurred in those previously immunized, raising the question of whether a genetic difference exists between the wild-type measles virus circulating in Indonesia and the vaccine virus being used. Such a difference may lead to the differences in the antigenicity of the wild-type and vaccine viruses, rendering the resulting antibody incapable of neutralizing the wild-type viruses. Based on the above, this study is aimed to demonstrate the extent of genetic and antigenic differences between the wild-type and vaccine measles viruses. We conducted an experimental laboratory study to sequence the N, H, and F genes of the wild-type measles viruses (G2, G3, and D9) and the CAM-70 vaccine virus. To show antigenic differences, the wild-type viruses (G2, G3, and D9) and the CAM-70 and Schwarz viruses were injected to BALB/c mice. Serum antibodies of the mice were analyzed using ELISA, cross-neutralization test, and immunoblotting using antigens from the respective viruses. Results of this study showed that the wild-type and the vaccine viruses differ in the sequence of the N gene by 73-79 nucleotides, resulting in amino acid substitution of 17-24 residues; the H gene by 60-99 nucleotides, resulting in amino acid substitution of 13-29 residues; the F gene by 71-88 nucleotides, resulting in amino acid substitution of 4-3 I residues. Differences between the wild-type and the CAM-70 and Schwarz vaccine viruses were also found in the epitope site of the CTL and antibodies, which are important to virus antigenicity. We conclude that a significant difference in antigenicity exists between the wild-type measles viruses circulating in Indonesia with the CAM-70 measles virus. We also found the immunogenicity of the CAM-70 and Schwarz vaccine viruses to be lower than that of the wild-type viruses."