Abstract
BackgroundMaturation inhibitors are a new class of antiretroviral drugs. Bevirimat (BVM) was the first substance in this class of inhibitors entering clinical trials. While the inhibitory function of BVM is well established, the molecular mechanisms of action and resistance are not well understood. It is known that mutations in the regions CS p24/p2 and p2 can cause phenotypic resistance to BVM. We have investigated a set of p24/p2 sequences of HIV-1 of known phenotypic resistance to BVM to test whether BVM resistance can be predicted from sequence, and to identify possible molecular mechanisms of BVM resistance in HIV-1.ResultsWe used artificial neural networks and random forests with different descriptors for the prediction of BVM resistance. Random forests with hydrophobicity as descriptor performed best and classified the sequences with an area under the Receiver Operating Characteristics (ROC) curve of 0.93 ± 0.001. For the collected data we find that p2 sequence positions 369 to 376 have the highest impact on resistance, with positions 370 and 372 being particularly important. These findings are in partial agreement with other recent studies. Apart from the complex machine learning models we derived a number of simple rules that predict BVM resistance from sequence with surprising accuracy. According to computational predictions based on the data set used, cleavage sites are usually not shifted by resistance mutations. However, we found that resistance mutations could shorten and weaken the α-helix in p2, which hints at a possible resistance mechanism.ConclusionsWe found that BVM resistance of HIV-1 can be predicted well from the sequence of the p2 peptide, which may prove useful for personalized therapy if maturation inhibitors reach clinical practice. Results of secondary structure analysis are compatible with a possible route to BVM resistance in which mutations weaken a six-helix bundle discovered in recent experiments, and thus ease Gag cleavage by the retroviral protease.
Highlights
Maturation inhibitors are a new class of antiretroviral drugs
BVM was the first drug of the new class of maturationinhibitors of HIV-1 that has reached phase II clinical trials
Several polymorphisms in p2 of HIV-1 hampered the sustained suppression of viral replication in these patients and conferred phenotypic resistance [7]
Summary
Bevirimat (BVM) was the first substance in this class of inhibitors entering clinical trials. We have investigated a set of p24/p2 sequences of HIV-1 of known phenotypic resistance to BVM to test whether BVM resistance can be predicted from sequence, and to identify possible molecular mechanisms of BVM resistance in HIV-1. HIV and Bevirimat Bevirimat (BVM) [1] belongs to a new class of anti-HIV substances that inhibit maturation of virus particles by preventing cleavage of precursor polyprotein by the retroviral protease (PR). BVM prevents the final cleavage of precursor protein p25 to p24 and p2, p25 proteins are accumulating in the immature virions These immature viral particles are not capable of transforming to an infectious stage, and the viral replication cycle is interrupted. Machine learning methods are built to cope with such complex associations
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