scholarly journals Molecular Footprint of Drug-Selective Pressure in a Human Immunodeficiency Virus Transmission Chain

2005 ◽  
Vol 79 (18) ◽  
pp. 11981-11989 ◽  
Author(s):  
Philippe Lemey ◽  
Inge Derdelinckx ◽  
Andrew Rambaut ◽  
Kristel Van Laethem ◽  
Stephanie Dumont ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Selective Pressure ◽  
Phylogenetic Analyses ◽  
Parallel Evolution ◽  
Multidrug Resistant ◽  
Resistance Mutations ◽  
Fixation Rate ◽  
Codon Substitution ◽  
Transmission Chain ◽  
Immunodeficiency Virus

ABSTRACT Known human immunodeficiency virus (HIV) transmission histories are invaluable models for investigating the evolutionary and transmission dynamics of the virus and to assess the accuracy of phylogenetic reconstructions. Here we have characterized an HIV-1 transmission chain consisting of nine infected patients, almost all of whom were treated with antiviral drugs at later stages of infection. Partial pol and env gp41 regions of the HIV genome were directly sequenced from plasma viral RNA for at least one sample from each patient. Phylogenetic analyses in pol using likelihood methods inferred an evolutionary history not fully compatible with the known transmission history. This could be attributed to parallel evolution of drug resistance mutations resulting in the incorrect clustering of multidrug-resistant virus. On the other hand, a fully compatible phylogenetic tree was reconstructed from the env sequences. We were able to identify and quantify the molecular footprint of drug-selective pressure in pol using maximum likelihood inference under different codon substitution models. An increased fixation rate of mutations in the HIV population of the multidrug-resistant patient was demonstrated using molecular clock modeling. We show that molecular evolutionary analyses, guided by a known transmission history, can reveal the presence of confounding factors like natural selection and caution should be taken when accurate descriptions of HIV evolution are required.

scholarly journals Selection of High-Level Resistance to Human Immunodeficiency Virus Type 1 Protease Inhibitors

2003 ◽  
Vol 47 (2) ◽  
pp. 759-769 ◽  
Author(s):  
Terri Watkins ◽  
Wolfgang Resch ◽  
David Irlbeck ◽  
Ronald Swanstrom
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitors ◽  
Human Immunodeficiency Virus Type ◽  
Selective Pressure ◽  
Cross Resistance ◽  
Resistance Mutations ◽  
Immunodeficiency Virus ◽  
High Level ◽  
Level Resistance

ABSTRACT Protease inhibitors represent some of the most potent agents available for therapeutic strategies designed to inhibit human immunodeficiency virus type 1 (HIV-1) replication. Under certain circumstances the virus develops resistance to the inhibitor, thereby negating the benefits of this therapy. We have carried out selections for high-level resistance to each of three protease inhibitors (indinavir, ritonavir, and saquinavir) in cell culture. Mutations accumulated over most of the course of the increasing selective pressure. There was significant overlap in the identity of the mutations selected with the different inhibitors, and this gave rise to high levels of cross-resistance. Virus particles from the resistant variants all showed defects in processing at the NC/p1 protease cleavage site in Gag. Selections with pairs of inhibitors yielded similar patterns of resistance mutations. A virus that could replicate at near-toxic levels of the three protease inhibitors combined was selected. The pro sequence of this virus was similar to that of the viruses that had been selected for high-level resistance to each of the drugs singly. Finally, a molecular clone carrying the eight most common resistance mutations seen in these selections was characterized. The sequence of this virus was relatively stable during selection for revertants in spite of displaying poor processing at the NC/p1 site and having significantly reduced fitness. These results reveal patterns of drug resistance that extend to near the limits of attainable selective pressure with these inhibitors and confirm the patterns of cross-resistance for these three inhibitors and the attenuation of virion protein processing and fitness that accompanies high-level resistance.

Multidrug Resistant Mycobacterium tuberculosis in Patients with Human Immunodeficiency Virus Infection

CHEST Journal ◽  
1992 ◽  
Vol 102 (3) ◽  
pp. 797-801 ◽  
Author(s):  
Christopher P. Busillo ◽  
Klaus-Dieter Lessnou ◽  
Veraaf Sanjana ◽  
Sarantos Soumakis ◽  
Morton Davidson ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mycobacterium Tuberculosis ◽  
Virus Infection ◽  
Human Immunodeficiency Virus Infection ◽  
Multidrug Resistant ◽  
Immunodeficiency Virus

scholarly journals The Fitness Cost of Mutations Associated with Human Immunodeficiency Virus Type 1 Drug Resistance Is Modulated by Mutational Interactions

2006 ◽  
Vol 81 (6) ◽  
pp. 3037-3041 ◽  
Author(s):  
Mian-er Cong ◽  
Walid Heneine ◽  
J. Gerardo García-Lerma
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Fitness Cost ◽  
Resistance Mutations ◽  
Drug Pressure ◽  
Critical Determinant ◽  
Immunodeficiency Virus ◽  
Cost Of Resistance

ABSTRACT It is generally accepted that the fitness cost of resistance mutations plays a role in the persistence of transmitted drug-resistant human immunodeficiency virus type 1 and that mutations that confer a high fitness cost are less able to persist in the absence of drug pressure. Here, we show that the fitness cost of reverse transcriptase (RT) mutations can vary within a 72-fold range. We also demonstrate that the fitness cost of M184V and K70R can be decreased or enhanced by other resistance mutations such as D67N and K219Q. We conclude that the persistence of transmitted RT mutants might range widely on the basis of fitness and that the modulation of fitness cost by mutational interactions will be a critical determinant of persistence.

scholarly journals Drug‐Selected Resistance Mutations and Non‐B Subtypes in Antiretroviral‐Naive Adults with Established Human Immunodeficiency Virus Infection

2003 ◽  
Vol 188 (7) ◽  
pp. 986-991 ◽  
Author(s):  
George J. Hanna ◽  
Henri U. Balaguera ◽  
Kenneth A. Freedberg ◽  
Barbara G. Werner ◽  
Kathleen A. Steger Craven ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Virus Infection ◽  
Human Immunodeficiency Virus Infection ◽  
Resistance Mutations ◽  
Immunodeficiency Virus

scholarly journals Selective Excision of AZTMP by Drug-Resistant Human Immunodeficiency Virus Reverse Transcriptase

2001 ◽  
Vol 75 (10) ◽  
pp. 4832-4842 ◽  
Author(s):  
Paul L. Boyer ◽  
Stefan G. Sarafianos ◽  
Edward Arnold ◽  
Stephen H. Hughes
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Nucleoside Analogs ◽  
Azido Group ◽  
Resistance Mutations ◽  
Immunodeficiency Virus ◽  
Azt Resistance ◽  
Hiv 1

ABSTRACT Two distinct mechanisms can be envisioned for resistance of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) to nucleoside analogs: one in which the mutations interfere with the ability of HIV-1 RT to incorporate the analog, and the other in which the mutations enhance the excision of the analog after it has been incorporated. It has been clear for some time that there are mutations that selectively interfere with the incorporation of nucleoside analogs; however, it has only recently been proposed that zidovudine (AZT) resistance can involve the excision of the nucleoside analog after it has been incorporated into viral DNA. Although this proposal resolves some important issues, it leaves some questions unanswered. In particular, how do the AZT resistance mutations enhance excision, and what mechanism(s) causes the excision reaction to be relatively specific for AZT? We have used both structural and biochemical data to develop a model. In this model, several of the mutations associated with AZT resistance act primarily to enhance the binding of ATP, which is the most likely pyrophosphate donor in the in vivo excision reaction. The AZT resistance mutations serve to increase the affinity of RT for ATP so that, at physiological ATP concentrations, excision is reasonably efficient. So far as we can determine, the specificity of the excision reaction for an AZT-terminated primer is not due to the mutations that confer resistance, but depends instead on the structure of the region around the HIV-1 RT polymerase active site and on its interactions with the azido group of AZT. Steric constraints involving the azido group cause the end of an AZT 5′-monophosphate-terminated primer to preferentially reside at the nucleotide binding site, which favors excision.

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