Strains Of HIV-1 CRF07_BC And B 'evolution Of Drug Resistance

HIV-1CRF07_BC and B’ are the main epidemic strains in china. Anti-viral therapy has effectively reduce the transmission of aids, prolong the survival of life, however, antiviral treatment failure correspondingly increased owing to drug resistance, which has greatly affected the effects of treatment and increased the risk of drug-resistance strains transmission. The drug resistance and the complex evolution of HIV-1under the drug and immune pressure have posed the change to the traditional drug resistance analysis, especially for the non-B subtypes circulating in china. So, this study was carried out systematically from the view of viral genetic variations. Firstly, this study developed a software package CorMut for correlated mutation analysis, and then we did the analysis for mutation covariation and drug resistance pathway of HIV-1CRF07_BC reverse transcriptase during antiretroviral therapy, as well as the influence of HIV-1variation to treatment effect in former plasma/blood donors. This study will help us understand the distinct drug resistance evolution patterns and the roles of polymorphisms in drug resistance development, related studies will provide crucial support to design multiple drug combination for therapy.1. The development and application of software for computing correlatedmutations based on selection pressureCorrelated mutations constitute a fundamental idea in evolutionary biology, and understanding correlated mutations will, in turn, facilitate the understanding of the genetic mechanisms governing evolution. We developed an R/Bioconductor package to detect the correlated mutations among positive selection sites by combining Ka/Ks ratio and correlated mutations analysis. CorMut is an R package designed to compute correlated mutations in the unit of codon or amino acid mutation.CorMut incorporates three classical methods to detect correlated mutations, including conditional selection pressure, mutual information and Jaccard index. The computation for correlated mutations consists of two steps:First, the positive selection sites are detected using the selection pressure-based method. Second, the mutation correlations are computed among the positive selection sites using the three methods described above. CorMut also enables the comparison of correlated mutations between two different evolutionary conditions. CorMut is released under the GNU General Public License within Bioconductor project, and freely available at following website http://bioconductor.org/packages/release/bioc/html/CorMut.html, and now CorMut has been downloaded more than2000.2. Mutation covariation of HFV-1CRF07_BC reverse transcriptase during antiretroviral therapyAs an epidemic recombinant subtype in China, the variation of HTV-1CRF07_BC under antiretroviral therapy (ART) has not been completely understood. The changes of mutation covariation in the reverse transcriptase (RT) and protease (PR) of HIV-1CRF07_BC were analyzed by comparing the552treatment-naive patients and261treatment patients under ART with zidothymidine (AZT)/lamivudine (3TC)/nevirapine (NVP) or AZT/3TC/efavirenz (EFV). Meanwhile, the stratified networks were used to display the mutation covariation.At first, three types of featured mutations for RT and PR were identified. These included treatment-associated mutations, treatment-agonistic mutations and overlapping polymorphisms. Ten pairs of significant correlated mutations were found between6treatment-associated mutations (K103N, M184V, Q197K, G190A, Y181C and M230L) and5overlapping polymorphisms (A36E, R135I, R277K, L283I and D291E). Meanwhile, a pair of correlated mutation between treatment-associated mutations (I132L) and overlapping polymorphisms (L101) for PR was also detected. Finally, overlapping polymorphisms for RT and PR were both found to have significant correlations with treatment-associated mutations, indicating the possible association between polymorphisms and drug resistance. The mutation covariations for RT and PR of HIV-1subtype B under the same regimens were also analyzed, and we found that CRF07_BC showed a distinct pattern of mutation covariation compared with subtype B.Some polymorphisms may play crucial roles in the development of drug resistance in HIV-1CRF07_BC. The analysis could help reveal the specific evolution of HIV-1CRF07_BC under ART, and the information might be useful for improving the efficacy of drug combinations.3. Resistance evolutionary pathway analysis of HTV-1CRF07_BC reverse transcriptaseWe studied the resistance evolution pathway of HIV-1CRF07_BC, a major circulating recombinant form in China, under drug selection pressure, and made a comparison with B subtype under the same regimens. Based on the reverse transcriptase region of CRF07_BC HIV-1from588treatment-naive and274treatment patients, we have used selection pressure based method to select resistance-associated mutations, and Bayesian network to construct the resistance evolutionary pathway under antiretroviral therapy. Meanwhile, we also construct the resistance evolutionary pathway for B subtype with the same regimens using the data from HIV resistance database, and made a comparison with CRF07_BC. We have identified the major resistance mutations for CRF07_BC, including K103N, Q197K, V179D and Y188L. While for B subtype, the major resistance mutations include M184V, K103N, Y181C, T69N, G190A, K238T, Y188H and P225H. Much difference was observed between these two classes. However, the classical TMA1(41L,210W and215Y) and TMA2(67N,70R and219E/Q) pathways exist in both pathways. As different from B subtype, the predicted major drug resistance mutations for CRF07_BC did not contain TAM-related mutations, and the relationship between nucleoside reverse transcriptase inhibitor-related mutations and non-nucleoside reverse transcriptase inhibitor-related mutations showed strong dependence. HIV-1CRF07_BC showed distinctive resistance evolutionary pathway, the mutations K103N, Q197K, V179D and Y188L were the major resistance mutations, and different resistance evolutionary pathways were observed between HTV-1CRF07_BC and B subtype.4. The influence of HIV-1genome variation to therapy effect in plasma donors infected with HIV-1As main epidemic subtype, the drug resistance of HTV-1B’ was rarely reported, the resistance evolution under ART, especially the dynamic genetic variation and its relation to long-term therapy effect need further investigate. We first transform the cohort data, sourcing from Henan and Anhui, into the cross-sectional data, then compare HIV-1RT region between the treatment-naive patients and treatment patients under ART, then identified42resistance-related mutations and mutation correlations. After that we investigate the dynamics of resistance-related mutations and mutation correlations and its relation to therapy effect in cohort view. At first, three types of featured mutations for RT were identified. These included treatment-associated mutations, treatment-agonistic mutations and overlapping polymorphisms, and then we constructed the correlated mutation network based on these features mutation.17pairs of significant correlated mutations were found between treatment-associated mutations and overlapping polymorphisms. This evidence further indicated that some polymorphisms may play crucial roles in the development of drug resistance. These correlated mutations can be basically divided into two parts after cluster analysis:those gradually increased and those increased first and then decreased.The polymorphisms in RT region may influence the resistance and virological failure, our results indicated there exist significant negative correlation between the number of polymorphisms and the time to virological failure, while the correlation between the number of polymorphisms and the time to resistance was not significant. In addition, we observed the influence of these polymorphisms to the appearance of resistance mutations. We screened16such polymorphisms and resistance-related mutations pairs. This result indicated the influence of polymorphisms in RT region to HIV-1drug resistance and virological failure, and polymorphisms may be considered before designing therapy regimens to avoid the emerging of some resistance mutations.