Molecular modeling studies of dihydro-alkyloxy-benzyl-oxopyrimidines (DABOs) as non-nucleoside inhibitors of HIV-1 reverse transcriptase using 3D-QSAR, Topomer CoMFA and molecular docking simulations

RSC Advances ◽  
2015 ◽  
Vol 5 (18) ◽  
pp. 13754-13761 ◽  
Author(s):  
Minghui Dong ◽  
Yujie Ren
Keyword(s):  
Reverse Transcriptase ◽  
Immune Deficiency Syndrome ◽  
3D Qsar ◽  
Deficiency Syndrome ◽  
Docking Simulations ◽  
Immunodeficiency Virus ◽  
Molecular Modeling Studies ◽  
Nucleoside Inhibitors ◽  
Hiv 1

The human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is generally regarded as a target for the treatment of acquired immune deficiency syndrome (AIDS).

scholarly journals The origin of acquired immune deficiency syndrome: Darwinian or Lamarckian?

2001 ◽  
Vol 356 (1410) ◽  
pp. 877-887 ◽  
Author(s):  
Tom Burr ◽  
J. M. Hyman ◽  
Gerald Myers
Keyword(s):  
Immune Deficiency ◽  
Simulated Data ◽  
Immune Deficiency Syndrome ◽  
Acquired Immune Deficiency Syndrome ◽  
Deficiency Syndrome ◽  
Darwinian Evolution ◽  
Immunodeficiency Virus ◽  
Acquired Immune Deficiency ◽  
Hiv 1

The subtypes of human immunodeficiency virus type 1 (HIV–1) group M exhibit a remarkable similarity in their between–subtype distances, which we refer to as high synchrony. The shape of the phylogenetic tree of these subtypes is referred to as a sunburst to distinguish it from a simple star phylogeny. Neither a sunburst pattern nor a comparable degree of symmetry is seen in a natural process such as in feline immunodeficiency virus evolution. We therefore have undertaken forward–process simulation studies employing coalescent theory to investigate whether such highly synchronized subtypes could be readily produced by natural Darwinian evolution. The forward model includes both classical (macro) and molecular (micro) epidemiological components. HIV–1 group M subtype synchrony is quantified using the standard deviation of the between–subtype distances and the average of the within–subtype distances. Highly synchronized subtypes and a sunburst phylogeny are not observed in our simulated data, leading to the conclusion that a quasi–Lamarckian, punctuated event occurred. The natural transfer theory for the origin of human acquired immune deficiency syndrome (AIDS) cannot easily be reconciled with these findings and it is as if a recent non–Darwinian process took place coincident with the rise of AIDS in Africa.

scholarly journals The earliest cases of human immunodeficiency virus type 1 group M in Congo-Kinshasa, Rwanda and Burundi and the origin of acquired immune deficiency syndrome

2001 ◽  
Vol 356 (1410) ◽  
pp. 923-925 ◽  
Author(s):  
Daniel Vangroenweghe
Keyword(s):  
Immune Deficiency ◽  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Immune Deficiency Syndrome ◽  
Acquired Immune Deficiency Syndrome ◽  
Deficiency Syndrome ◽  
Immunodeficiency Virus ◽  
Acquired Immune Deficiency ◽  
Hiv 1

The early cases of acquired immune deficiency syndrome and human immunodeficiency virus type 1 (HIV–1) infection in the 1960s and 1970s in Congo–Kinshasa (Zaire), Rwanda and Burundi are reviewed. These countries appear to be the source of the HIV–1 group M epidemic, which then spread outwards to neighbouring Tanzania and Uganda in the east, and Congo–Brazzaville in the west. Further spread to Haiti and onwards to the USA can be explained by the hundreds of single men from Haiti who participated in the UNESCO educational programme in the Congo between 1960 and 1975.

scholarly journals Using human immunodeficiency virus type 1 sequences to infer historical features of the acquired immune deficiency syndrome epidemic and human immunodeficiency virus evolution

2001 ◽  
Vol 356 (1410) ◽  
pp. 855-866 ◽  
Author(s):  
Karina Yusim ◽  
Martine Peeters ◽  
Oliver G. Pybus ◽  
Tanmoy Bhattacharya ◽  
Eric Delaporte ◽  
...  
Keyword(s):  
Immune Deficiency ◽  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Immune Deficiency Syndrome ◽  
Acquired Immune Deficiency Syndrome ◽  
Deficiency Syndrome ◽  
Immunodeficiency Virus ◽  
Acquired Immune Deficiency ◽  
Hiv 1

In earlier work, human immunodeficiency virus type 1 (HIV–1) sequences were analysed to estimate the timing of the ancestral sequence of the main group of HIV–1, the virus that is responsible for the acquired immune deficiency syndrome pandemic, yielding a best estimate of 1931 (95% confidence interval of 1915–1941). That work will be briefly reviewed, outlining how phylogenetic tools were extended to incorporate improved evolutionary models, how the molecular clock model was adapted to incorporate variable periods of latency, and how the approach was validated by correctly estimating the timing of two historically documented dates. The advantages, limitations, and assumptions of the approach will be summarized, with particular consideration of the implications of branch length uncertainty and recombination. We have recently undertaken new phylogenetic analysis of an extremely diverse set of human immunodeficiency virus envelope sequences from the Democratic Republic of the Congo (the DRC, formerly Zaire). This analysis both corroborates and extends the conclusions of our original study. Coalescent methods were used to infer the demographic history of the HIV–1 epidemic in the DRC, and the results suggest an increase in the exponential growth rate of the infected population through time.

scholarly journals Line Probe Assay for Detection of Human Immunodeficiency Virus Type 1 Mutations Conferring Resistance to Nucleoside Inhibitors of Reverse Transcriptase: Comparison with Sequence Analysis

1998 ◽  
Vol 36 (7) ◽  
pp. 2143-2145 ◽  
Author(s):  
Diane Descamps ◽  
Vincent Calvez ◽  
Gilles Collin ◽  
Agnès Cécille ◽  
Cristian Apetrei ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Sequence Analysis ◽  
Reverse Transcriptase ◽  
Line Probe Assay ◽  
Immunodeficiency Virus ◽  
Mixed Populations ◽  
Probe Assay ◽  
Nucleoside Inhibitors ◽  
Hiv 1

We compared the line probe assay (LiPA) to sequence analysis for the detection of mutations conferring resistance to nucleoside inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). Plasma samples from 40 patients who had received zidovudine, dideoxyinosine, and dideoxycytosine, alone or in combination, and who were enrolled in the ALTIS 2 clinical trial (lamivudine [3TC] plus stavudine) were tested at enrollment and at week 24. RT PCR products from plasma were used for LiPA, and DNA was used for sequence analysis. LiPA gave uninterpretable results for 8.5% of the analyzed codons corresponding to 63 samples, mainly for codons 41, 69, and 70. Several minor discrepancies between the two methods occurred, mainly due to the ability of LiPA to detect mixed populations while sequence analyses detect a single homogeneous population. LiPA is suitable for detecting mixed populations and easy to implement in clinical laboratories and might be useful for epidemiological surveys of primary HIV-1 resistance.

scholarly journals Novel Nonnucleoside Inhibitors That Select Nucleoside Inhibitor Resistance Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase

2006 ◽  
Vol 50 (8) ◽  
pp. 2772-2781 ◽  
Author(s):  
Zhijun Zhang ◽  
Michelle Walker ◽  
Wen Xu ◽  
Jae Hoon Shim ◽  
Jean-Luc Girardet ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Immunodeficiency Virus ◽  
Nonnucleoside Inhibitors ◽  
Rt Inhibitors ◽  
Hiv 1 ◽  
M184v Mutation

ABSTRACT Mutations in and around the catalytic site of the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) are associated with resistance to nucleoside RT inhibitors (NRTIs), whereas changes in the hydrophobic pocket of the RT are attributed to nonnucleoside RT inhibitor (NNRTI) resistance. In this study, we report a novel series of nonnucleoside inhibitors of HIV-1, exemplified by VRX-329747 and VRX-413638, which inhibit both NNRTI- and NRTI-resistant HIV-1 isolates. Enzymatic studies indicated that these compounds are HIV-1 RT inhibitors. Surprisingly, however, following prolonged (6 months) tissue culture selection, this series of nonnucleoside inhibitors did not select NNRTI-resistant mutations in HIV-1 RT. Rather, four mutations (M41L, A62T/V, V118I, and M184V) known to cause resistance to NRTIs and two additional novel mutations (S68N and G112S) adjacent to the catalytic site of the enzyme were selected. Although the M184V mutation appears to be the initial mutation to establish resistance, this mutation alone confers only a two- to fourfold decrease in susceptibility to VRX-329747 and VRX-413638. At least two additional mutations must accumulate for significant resistance. Moreover, while VRX-329747-selected viruses are resistant to lamivudine and emtricitabine due to the M184V mutation, they remain susceptible to zidovudine, stavudine, dideoxyinosine, abacavir, tenofovir, and efavirenz. These results directly demonstrate that VRX-329747 and VRX-413638 are novel nonnucleoside inhibitors of HIV-1 RT with the potential to augment current therapies.

The double mutation L109M and R448M of HIV-1 reverse transcriptase decreases fidelity of DNA synthesis by promoting mismatch elongation

2015 ◽  
Vol 396 (12) ◽  
pp. 1315-1323
Author(s):  
Bianca Heyn ◽  
Nicole Pogodalla ◽  
Susanne Brakmann
Keyword(s):  
Reverse Transcriptase ◽  
Dna Synthesis ◽  
Error Rate ◽  
Double Mutant ◽  
Dissociation Rate ◽  
Double Mutation ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Simultaneous Substitution

Abstract Changes of Leu109 and Arg448 of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) have as yet not been associated with altered fitness. However, in a recent study, we described that the simultaneous substitution of L109 and R448 by methionine leads to an error-producing polymerase phenotype that is not observed for the isolated substitutions. The double mutant increased the error rate of DNA-dependent DNA synthesis 3.1-fold as compared to the wildtype enzyme and showed a mutational spectrum with a fraction of 28% frameshift mutations and 48% transitions. We show here that weaker binding of DNA:DNA primer-templates as indicated by an increased dissociation rate constant (koff) could account for the higher frameshift error rate. Furthermore, we were able to explain the prevalence of transition mutations with the finding that HIV-1 RT variant L109M/R448M preferred misincorporation of C opposite A and elongation of C:A mismatches.

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