(step1) HIV drug 개발의 어려움 운영자 / 2005-09-21 12:51:40
HIV virus에 대한 항생제 개발이 어려운 이유는?
아래 a)중 1번이 제일 중요(reverse transcriptase의 proofreading기능의 취약함으로 mutation이 잘 일어나므로)
a) Genetic basis of resistance:
i) Mutations in the genome of RNA viruses occur with high frequency because RNA polymerase, unlike DNA polymerase, does not have a proof reading mechanism to correct errors in transcription during replication. On average, the reverse transcriptase of HIV makes 1 error per 10 000 bases copied. Thus, with 10 billion (1010) HIV-1 virus particles produced every day and each genome containing 1 mutation, it is not difficult to imagine that swarms of quasispecies (i.e. genetically distinct viral variants occurring in the same individual) are generated con-taining every possible drug mutation.
ii) Recombination: Additional genetic variation is produced by the recombining of the genomes of viruses from different quasispecies. This may occur when 2 viruses simultaneously infect the same cell and segments of their transcribed genes are recombined into the progeny virus' genome.
b) Selection and amplification: Mutants conferring drug resistance may be the result of one or a few nucleotide substitutions and are present in viruses in low numbers even before they come into contact with any antiviral drug. They may be less competent in their repli-cative ability and their transmissi-bility than the wild-type virus in the absence of the drug. (This is seen particularly with herpesviruses resistant to acyclovir.) However, the selective pressure of the antiviral drug selects for resistant mutants which are fitter within the environ-ment containing the drug, resulting in amplification of the virus. Further amplification may be due to the reduction of immune surveillance and consequently an increase in the replication rate of the virus.
c) Antiviral resistance patterns: With some antiretroviral drugs, high level resistance is conferred by a single mutation, for example lamivudine and the non-nucleoside reverse transcriptase inhibitors (NNRTI) e.g. nevirapine. Monotherapy with these agents results in high level resistance within a month of treatment. With other antiretro-virals, e.g. zidovudine and the protease inhibitors, resistance is also inevitable but is more complex, requiring the accumulation of three or more resistance mutants, and monotherapy with these agents produces resistance after 6 or more months. In some cases, a mutant conferring resistance to 1 drug may re-sensitize the virus to another anti-retroviral. For example, a mutation at position 184 of the reverse trans-criptase genome confers high grade resistance to lamivudine, but at the same time resensitizes the virus to zidovudine. (This is partially the basis for the efficacy of the combination of zidovudine and lamivudine.)
d) Transmissibility of drug resistant HIV: Some of the earlier studies demonstrated that zidovudine resis-tant HIV may have reduced replica-tive capacity and therefore reduced transmissibility than wild-type virus in the absence of the drug. Since then, transmission of drug-resistant HIV has been observed via the sexual (homosexual and hetero-sexual) vertical and parenteral routes. Drug-resistant mutant HIV has also been detected in several studies of individuals soon after seroconversion.
