AEGiS-14IAC: Complex mutation spectrum of codon changes in the protease and reverse transcriptase genes, and genomic instability: in HIV-1 infected patients treated with HAART.

14th International AIDS Conference

Barcelona, Spain - July 7-12, 2002

Complex mutation spectrum of codon changes in the protease and reverse transcriptase genes, and genomic instability: in HIV-1 infected patients treated with HAART.

Int Conf AIDS 2002 Jul 7-12; 14:(abstract no. A10065)

McGhee EM, Voss JG, Holzemer WL
University, San Francisco, United States

BACKGROUND: Several studies have shown genetic damage and mutational changes in the virus profile can impair treatment of HIV-1 infection. Failure to adhere to highly active antiretroviral therapy (HAART) can lead to subtheraputic drug levels which has been associated with increased genotoxicity and drug resistance. We are currently invesitgating the frequency of complex codon changes in the protease (PR) and reverse transcriptase (RT) genes and Genomic instability by chromosome analysis, using HAART-treated patient's blood samples.

METHODS: Genotype profiles of HIV-1 patients undergoing HAART (N=30) were studied. The base sequence changes were determined by polymerase chain reaction using RNA extracts. We also investigated genomic instability events by assaying for chromosomal damage in cultures of infected T-lymphocytes. The mutation frequency was calculated by SPSS10.0 analysis.

RESULTS: HIV-1 patients treated with HAART exhibit mutations in viral PR and RT genes at multiple codon sites. In the PR codons, we observed the following mutations: [codon(%)]: wildtype: 63(57%), 77(20%); silent, 18(27%), 67(17%), 68(20%), 94(23%), 97(17%); polymorphism, 37(80%). 62(20%), 64(20%), 69(13%), 72(13), 93(13%); unexpected, 10(3%), 33(3%), 63(20%), 71(7%). In the RT codons, we observed the following mutations [codon(%)]: wild type, 67(10%), 103(50%), 184(50%); silent, 77(20%), 97(63%), 119(33%), 138(20%), 204(93%), 219(15%), 235(7%), 246(23%); polymorphism, 122(60%),162(23%), 174(20%), 200(33%), 211(46%), 214(73%), 245(46%); unexpected, 41(3%), 98(3%), 101(3%), 179(7%), 190(7%). In infected T-lymphocytes cultures we noted chromosomal damage, increased cell death and abnormal cell cycle regulation.

CONCLUSIONS: Our preliminary data show a complex mutation distribution in the viral PR and RT genes. These findings may indicate important changes that are contributing to increased drug resistance and delayed genetic/genomic instability.

Keywords: AEGIS, RNA-Directed DNA Polymerase, Antiretroviral Therapy, Highly Active, HIV-1, Codon, HIV Protease, HIV Infections, Mutation, Endopeptidases, Genotype, Human, genetics

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A10065